<br>CD22L 与胰岛素的结合减弱了胰岛素特异性 B 细胞活化,Bioconjugate Chemistry

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CD22L 与胰岛素的结合减弱了胰岛素特异性 B 细胞活化
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2023-10-26 , DOI: 10.1021/acs.bioconjchem.3c00391
Kyle D Apley ₁ , Amber S Griffith ₂ , Grant M Downes ₃ , Patrick Ross ₄ , Mark P Farrell ₄ , Peggy Kendall ₂ , Cory J Berkland _{1,

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Affiliation

胰岛反应性 B 淋巴细胞通过向胰岛破坏性 T 细胞呈递抗原来促进 1 型糖尿病（T1D）。Teplizumab 是一种抗 CD3 单克隆抗体，可延缓高危患者的 T1D 发病，但需要额外的疗法来完全预防该疾病。因此，双功能分子被设计为通过将 B 细胞抑制受体 CD22 （即 CD22L）的配体与胰岛素偶联来选择性抑制促进 T1D 的抗胰岛素 B 细胞，从而允许这些分子同时与抗胰岛素 B 细胞受体（BCR）和 CD22 结合。合成了两个原型：4 臂 PEG 骨架上的 2：2 胰岛素-CD22L 偶联物，以及 1：1 胰岛素-CD22L 直接偶联物。表达抗胰岛素 BCR 的转基因小鼠（125Tg^SD）为体外检测提供了细胞。将细胞与构建体一起培养 3 天，然后通过流式细胞术进行评估。使用抗 CD40 模拟 T 细胞帮助复制孔。2 胰岛素 4 臂 PEG 对照引起强劲的增殖和激活诱导的 CD86 上调。抗 CD40 进一步增强了这些作用。这可能表明当抗原被 PEG 骨架栓系时，就会发生 BCR 交联，因为单独的可溶性胰岛素没有效果。通过 2：2 胰岛素-CD22L 偶联物添加 CD22L 可将 B 细胞特性恢复到对照的特性，而不会产生额外的有益效果。相比之下，在存在抗 CD40 的情况下，1：1 胰岛素-CD22L 直接偶联物显着降低了抗胰岛素 B 细胞增殖。单独的 CD22L 没有影响，并且构建体不会影响 WT B 细胞。因此，多价抗原构建体倾向于激活抗胰岛素 B 细胞，而单体抗原-CD22L 偶联物响应模拟 T 细胞帮助减少 B 细胞活化，并减少致病性 B 细胞数量，而不会伤害正常细胞。因此，单体抗原-CD22L 偶联物值得进一步研究，并且可能有望成为临床前试验的候选者，以在不诱导免疫缺陷的情况下预防 T1D。

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CD22L Conjugation to Insulin Attenuates Insulin-Specific B Cell Activation

Pancreatic islet-reactive B lymphocytes promote Type 1 diabetes (T1D) by presenting an antigen to islet-destructive T cells. Teplizumab, an anti-CD3 monoclonal, delays T1D onset in patients at risk, but additional therapies are needed to prevent the disease entirely. Therefore, bifunctional molecules were designed to selectively inhibit T1D-promoting anti-insulin B cells by conjugating a ligand for the B cell inhibitory receptor CD22 (i.e., CD22L) to insulin, which permit these molecules to concomitantly bind to anti-insulin B cell receptors (BCRs) and CD22. Two prototypes were synthesized: 2:2 insulin–CD22L conjugate on a 4-arm PEG backbone, and 1:1 insulin–CD22L direct conjugate. Transgenic mice (125Tg^SD) expressing anti-insulin BCRs provided cells for in vitro testing. Cells were cultured with constructs for 3 days, then assessed by flow cytometry. Duplicate wells with anti-CD40 simulated T cell help. A 2-insulin 4-arm PEG control caused robust proliferation and activation-induced CD86 upregulation. Anti-CD40 further boosted these effects. This may indicate that BCR-cross-linking occurs when antigens are tethered by the PEG backbone as soluble insulin alone has no effect. Addition of CD22L via the 2:2 insulin–CD22L conjugate restored B cell properties to that of controls without an additional beneficial effect. In contrast, the 1:1 insulin–CD22L direct conjugate significantly reduced anti-insulin B cell proliferation in the presence of anti-CD40. CD22L alone had no effect, and the constructs did not affect the WT B cells. Thus, multivalent antigen constructs tend to activate anti-insulin B cells, while monomeric antigen–CD22L conjugates reduce B cell activation in response to simulated T cell help and reduce pathogenic B cell numbers without harming normal cells. Therefore, monomeric antigen-CD22L conjugates warrant futher study and may be promising candidates for preclinical trials to prevent T1D without inducing immunodeficiency.

更新日期：2023-10-26

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