Targeting Stereotyped B Cell Receptors from Chronic Lymphocytic Leukemia Patients with Synthetic Antigen Surrogates
Targeting Stereotyped B Cell Receptors from Chronic Lymphocytic Leukemia Patients with Synthetic Antigen Surrogates
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DOI：
10.1074/jbc.m115.701656
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发表时间：
2016-04-01
影响因子：
4.8
通讯作者：
Kodadek, Thomas
中科院分区：
文献类型：
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作者：
Sarkar, Mohosin;Liu, Yun;Kodadek, Thomas
慢性淋巴细胞性白血病(CLL)是一种单个B细胞克隆在外周淋巴器官、骨髓和血液中持续增殖的疾病。DNA测序实验表明，约30%的CLL患者在重链和轻链的可变区具有高度同源性的抗原特异性B细胞受体(BCR)。其中包括许多最具侵袭性的病例，这些病例具有IGHV未突变的BCR，其序列并未明显偏离生殖系。这表明了一种个性化的治疗策略，在这种策略中，毒素或免疫效应器功能被选择性地传递到致病的B细胞，而不是健康的B细胞。为了执行这一策略，需要血清稳定的类药物化合物，能够靶向定型亚群中大多数或所有患者的抗原结合部位。我们在这里通过发现具有侵略性的、刻板印象的7P子集的CLL BCR的选择性、高亲和力配体来证明这种方法的可行性，这些配体与子集7P中的几个CLL患者的BCR交叉反应，但不与这个子集以外的患者的BCR交叉反应。
Chronic lymphocytic leukemia (CLL) is a disease in which a single B-cell clone proliferates relentlessly in peripheral lymphoid organs, bone marrow, and blood. DNA sequencing experiments have shown that about 30% of CLL patients have stereotyped antigen-specific B-cell receptors (BCRs) with a high level of sequence homology in the variable domains of the heavy and light chains. These include many of the most aggressive cases that have IGHV-unmutated BCRs whose sequences have not diverged significantly from the germ line. This suggests a personalized therapy strategy in which a toxin or immune effector function is delivered selectively to the pathogenic B-cells but not to healthy B-cells. To execute this strategy, serum-stable, drug-like compounds able to target the antigen-binding sites of most or all patients in a stereotyped subset are required. We demonstrate here the feasibility of this approach with the discovery of selective, high affinity ligands for CLL BCRs of the aggressive, stereotyped subset 7P that cross-react with the BCRs of several CLL patients in subset 7p, but not with BCRs from patients outside this subset.