Welt Rachel S, Welt Jonathan A, Kostyal David, Gangadharan Yamuna D, Raymond Virginia, Welt Sydney
American Museum of Natural History, New York, NY, USA.
Welt Bio-Molecular Pharmaceutical, LLC., Armonk, NY, USA.
Oncotarget. 2016 Nov 15;7(46):74701-74723. doi: 10.18632/oncotarget.12506.
The concept that the B-cell Receptor (BCR) initiates a driver pathway in lymphoma-leukemia has been clinically validated. Previously described unique BCR Ig-class-specific sequences (proximal domains (PDs)), are not expressed in serum Ig (sIg). As a consequence of sequence and structural differences in the membrane IgM (mIgM) µ-Constant Domain 4, additional epitopes distinguish mIgM from sIgM. mAbs generated to linear and conformational epitopes, restricted to mIgM and not reacting with sIgM, were generated despite the relative hydrophobicity of the PDm sequence. Anti-PD mAbs (mAb1, mAb2, and mAb3) internalize mIgM. Anti-mIgM mAb4, which recognizes a distinct non-ligand binding site epitope, mediates mIgM internalization, and in low-density cultures, growth inhibition, anti-clonogenic activity, and apoptosis. We show that mAb-mediated mIgM internalization generally does not interrupt BCR-directed cell growth, however, mAb4 binding to a non-ligand binding site in the mIgM PDm-μC4 domain induces both mIgM internalization and anti-tumor effects. BCR micro-clustering in many B-cell leukemia and lymphoma lines is demonstrated by SEM micrographs using these new mAb reagents. mAb4 is a clinical candidate as a mediator of inhibition of the BCR signaling pathway. As these agents do not bind to non-mIgM B-cells, nor cross-react to non-lymphatic tissues, they may spare B-cell/normal tissue destruction as mAb-drug conjugates.
B细胞受体（BCR）在淋巴瘤白血病中启动驱动途径这一概念已得到临床验证。先前描述的独特BCR Ig类特异性序列（近端结构域（PDs））在血清Ig（sIg）中不表达。由于膜IgM（mIgM）μ恒定结构域4中的序列和结构差异，额外的表位可区分mIgM和sIgM。尽管PDm序列具有相对疏水性，但仍产生了针对线性和构象表位的单克隆抗体（mAb），这些表位仅限于mIgM，不与sIgM反应。抗PD单克隆抗体（mAb1、mAb2和mAb3）使mIgM内化。识别独特非配体结合位点表位的抗mIgM单克隆抗体4介导mIgM内化，并且在低密度培养中，具有生长抑制、抗克隆活性和诱导凋亡的作用。我们表明，单克隆抗体介导的mIgM内化通常不会中断BCR导向的细胞生长，然而，单克隆抗体4与mIgM PDm-μC4结构域中的非配体结合位点结合会诱导mIgM内化和抗肿瘤作用。使用这些新的单克隆抗体制剂的扫描电子显微镜图像证明了许多B细胞白血病和淋巴瘤细胞系中的BCR微聚集。单克隆抗体4作为BCR信号通路抑制介质是一种临床候选药物。由于这些药物不与非mIgM B细胞结合，也不会与非淋巴组织发生交叉反应，作为单克隆抗体-药物偶联物，它们可能避免B细胞/正常组织的破坏。
