Oncotarget

Research Papers:

Specificity and biologic activities of novel anti-membrane IgM antibodies

Rachel S. Welt, Jonathan A. Welt, David Kostyal, Yamuna D. Gangadharan, Virginia Raymond and Sydney Welt _

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Oncotarget. 2016; 7:74701-74723. https://doi.org/10.18632/oncotarget.12506

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Abstract

Rachel S. Welt1, Jonathan A. Welt2, David Kostyal3, Yamuna D Gangadharan2, Virginia Raymond2,4 and Sydney Welt2

1 American Museum of Natural History, New York, NY, USA

2 Welt Bio-Molecular Pharmaceutical, LLC., Armonk, NY, USA

3 ARDL, Inc., Akron, OH, USA

4 Biogent, LLC., Armonk, NY, USA

Correspondence to:

Sydney Welt, email:

Keywords: monoclonal antibody, membrane IgM, B-cell receptor, leukemia, lymphoma

Received: January 31, 2016 Accepted: September 24, 2016 Published: October 09, 2016

Abstract

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.


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