a Bioanalytical and Discovery Analytical Sciences, Pharmaceutical Candidate Optimization, Research and Development , Bristol-Myers Squibb Company , Princeton , NJ , USA.
b Molecular Discovery Technologies, Research and Development , Bristol-Myers Squibb Company , Princeton , NJ , USA.
MAbs. 2018 Jan;10(1):95-103. doi: 10.1080/19420862.2017.1393595. Epub 2017 Nov 14.
TL1A, a tumor necrosis factor-like cytokine, is a ligand for the death domain receptor DR3. TL1A, upon binding to DR3, can stimulate lymphocytes and trigger secretion of proinflammatory cytokines. Therefore, blockade of TL1A/DR3 interaction may be a potential therapeutic strategy for autoimmune and inflammatory diseases. Recently, the anti-TL1A monoclonal antibody 1 (mAb1) with a strong potency in blocking the TL1A/DR3 interaction was identified. Here, we report on the use of hydrogen/deuterium exchange mass spectrometry (HDX-MS) to obtain molecular-level details of mAb1's binding epitope on TL1A. HDX coupled with electron-transfer dissociation MS provided residue-level epitope information. The HDX dataset, in combination with solvent accessible surface area (SASA) analysis and computational modeling, revealed a discontinuous epitope within the predicted interaction interface of TL1A and DR3. The epitope regions span a distance within the approximate size of the variable domains of mAb1's heavy and light chains, indicating it uses a unique mechanism of action to block the TL1A/DR3 interaction.
TL1A 是一种肿瘤坏死因子样细胞因子，是死亡结构域受体 DR3 的配体。TL1A 与 DR3 结合后，可刺激淋巴细胞并触发促炎细胞因子的分泌。因此，阻断 TL1A/DR3 相互作用可能是治疗自身免疫和炎症性疾病的一种潜在治疗策略。最近，发现了一种具有强阻断 TL1A/DR3 相互作用能力的抗 TL1A 单克隆抗体 1（mAb1）。在这里，我们报告使用氘代/氢交换质谱（HDX-MS）来获得 mAb1 在 TL1A 上的结合表位的分子水平细节。HDX 与电子转移解离 MS 相结合提供了残基水平的表位信息。HDX 数据集，结合溶剂可及表面积（SASA）分析和计算建模，揭示了 TL1A 和 DR3 预测相互作用界面内的不连续表位。表位区域跨越 mAb1 的重链和轻链的可变结构域的近似大小内的距离，表明它使用独特的作用机制来阻断 TL1A/DR3 相互作用。
