title: Specificity and biologic activities of novel anti-membrane IgM antibodies.
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.
authors.affiliation: American Museum of Natural History, New York, NY, USA.
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Welt
authors.affiliation: Welt Bio-Molecular Pharmaceutical, LLC., Armonk, NY, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Welt
authors.affiliation: ARDL, Inc., Akron, OH, USA.
authors.forename: David
authors.initials: D
authors.lastname: Kostyal
authors.affiliation: Welt Bio-Molecular Pharmaceutical, LLC., Armonk, NY, USA.
authors.forename: Yamuna D
authors.initials: YD
authors.lastname: Gangadharan
authors.affiliation: Welt Bio-Molecular Pharmaceutical, LLC., Armonk, NY, USA.|Biogent, LLC., Armonk, NY, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Raymond
authors.affiliation: Welt Bio-Molecular Pharmaceutical, LLC., Armonk, NY, USA.
authors.forename: Sydney
authors.initials: S
authors.lastname: Welt
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000918:Antibody Specificity / Q000276:immunology; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D006801:Humans; D006825:Hybridomas / Q000276:immunology; D015448:Leukemia, B-Cell / Q000276:immunology / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000378:metabolism; D051379:Mice; D010455:Peptides / Q000276:immunology; D011485:Protein Binding; D021381:Protein Transport; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D000939:Epitopes; D010455:Peptides; D011947:Receptors, Antigen, B-Cell; C044203:anti-IgM
keywords: B-cell receptor; leukemia; lymphoma; membrane IgM; monoclonal antibody