The Binding Specificity and Selective Antagonism of Vedolizumab, an Anti-α4β7 Integrin Therapeutic Antibody in Development for Inflammatory Bowel Diseases
The Binding Specificity and Selective Antagonism of Vedolizumab, an Anti-α4β7 Integrin Therapeutic Antibody in Development for Inflammatory Bowel Diseases
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DOI：
10.1124/jpet.109.153973
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发表时间：
2009-09-01
影响因子：
3.5
通讯作者：
Fedyk, Eric R.
中科院分区：
文献类型：
--
作者：
Soler, Dulce;Chapman, Tobias;Fedyk, Eric R.
Vedolizumab是一种人源化的单抗，专门针对α(4)β(7)整合素，调节胃肠道的炎症，而不会引起抗α(4)链单抗(如Natalizumab)的全身性免疫抑制。这种独特的药理学特征在很大程度上归因于四个决定因素。第一个决定因素是α(4)β(7)整合素对白细胞亚群的表达限制。Vedolizumab不与大多数记忆中的CD4(+)T淋巴细胞(60%)、中性粒细胞和大多数单核细胞结合。Vedolizumab结合水平最高的是人外周血记忆CD4(+)T淋巴细胞的一个亚群(类似于25%)，其中包括肠道归巢的白细胞介素17 T辅助淋巴细胞。Vedolizumab还与嗜酸性粒细胞高水平结合，低水平与幼稚T辅助淋巴细胞、幼稚和记忆性细胞毒性T淋巴细胞、B淋巴细胞、自然杀伤细胞和嗜碱性粒细胞结合；Vedolizumab以亚纳摩尔效力与记忆性CD4(+)T和B淋巴细胞结合(EC50=0.3-0.4 nM)。第二个决定因素是结合特异性；vedolizumab仅与α(4)β(7)整合素结合，而不与α(4)β(1)和α(E)β(7)整合素结合。第三个决定因素是选择性拮抗；vedolizumab选择性地抑制表达α(4)β(7)的细胞与粘膜地址素细胞黏附分子1(半数抑制浓度[IC50]=0.02-0.06 mU g/ml)和纤维连接蛋白(IC50=0.02 mU g/ml)的黏附，但不能抑制血管细胞黏附分子1。第四个决定因素是α(4)β(7)整合素功能的胃肠道特异性取向。Vedolizumab的这些药理特性，与α(4)β(7)整合素的胃肠导向功能相结合，可能最终会改善炎症性肠病患者的风险-受益情况。
Vedolizumab is a humanized monoclonal antibody that targets the alpha(4)beta(7) integrin exclusively, and modulates inflammation in the gastrointestinal tract without inducing the systemic immunosuppression that characterizes anti-alpha(4) chain monoclonal antibodies, such as natalizumab. This unique pharmacologic profile is largely attributable to four determinants. The first determinant is the restriction of the expression of the alpha(4)beta(7) integrin to subsets of leukocytes. Vedolizumab does not bind to the majority of memory CD4(+) T lymphocytes (60%), neutrophils, and most monocytes. The highest level of vedolizumab binding is to a subset (similar to 25%) of human peripheral blood memory CD4(+) T lymphocytes that include gut-homing interleukin 17 T-helper lymphocytes. Vedolizumab also binds to eosinophils at high levels, and to naive T-helper lymphocytes, naive and memory cytotoxic T lymphocytes, B lymphocytes, natural killer cells, and basophils at lower levels; vedolizumab binds to memory CD4(+) T and B lymphocytes with subnanomolar potency (EC50 = 0.3-0.4 nM). The second determinant is binding specificity; vedolizumab binds exclusively to the alpha(4)beta(7) integrin, and not to the alpha(4)beta(1) and alpha(E)beta(7) integrins. The third determinant is selective antagonism; vedolizumab selectively inhibits adhesion of alpha(4)beta(7)-expressing cells to mucosal addressin cell adhesion molecule 1 (median inhibition concentration [IC50] = 0.02-0.06 mu g/ml) and fibronectin (IC50 = 0.02 mu g/ml), but not vascular cell adhesion molecule 1. The fourth determinant is the gastrointestinal-specific tropism of the alpha(4)beta(7) integrin function. These pharmacologic properties of vedolizumab, in conjunction with the gastrointestinal tropism of alpha(4)beta(7) integrin function, may ultimately confer an improved risk-to-benefit profile for patients with inflammatory bowel diseases.