Abstract
Epithelial Ovarian Cancer (EOC) cells expression of a novel carbohydrate antigen was defined using a human VH4-34 encoded IgM monoclonal antibody (mAb216). MAb216 binds to a poly N-acetyllactosamine epitope expressed on B cells and kills normal and malignant B cells in vitro and in vivo. EOC patient ascites and EOC cell lines were used to study the anti tumor effect of mAb216. Various assays were used to characterize the epitope and demonstrate antibody-mediated binding and cytotoxicity in EOC. Drug and antibody combination effects were determined by calculating the combination index values using the Chou and Talalay method. MAb216 displays direct antibody mediated cytotoxicity on a population of human EOC tumor and ascites samples and EOC cell lines, which express high amounts of poly N-acetyllactosamine epitope, carried by CD147/CD98. Eighty four percent of patient samples, including platin resistant, had a tumor population that bound the monoclonal antibody. The binding pattern of mAb216 and mechanism of cytotoxicity was similar to that seen on normal and malignant B cells with unique general membrane disruption and “pore” formation. In vitro incubation with mAb216 and cisplatin enhanced killing of OVCAR3 cell line. In EOC cell lines percent cytotoxicity correlated with percent expression of epitope. Although in vitro data shows specific EOC cytotoxicity, for possible treatment of EOC MAb216 would need to be evaluated in a clinical trial with or without chemotherapy.
Highlights
MAb216 is a human derived IgM monoclonal antibody encoded in germline configuration by the immunoglobulin VH4-34 heavy chain gene
Many monoclonal antibody (mAb) derived from the VH4-34 heavy chain gene bind to a distinct straight chain poly n-acetyl lactosamine, referred to as the i/I antigen [2,3] and found on normal fetal red blood cells (RBCs) and mature B cells [4]
As we had access to epithelial ovarian carcinoma [Epithelial Ovarian Cancer (EOC)] patient samples including cancer cells from both primary and recurrent patients we focused on this tumor
Summary
MAb216 is a human derived IgM monoclonal antibody (mAb) encoded in germline configuration by the immunoglobulin VH4-34 heavy chain gene. VH4-34 encoded antibodies are found in plasma at low levels in normal subjects and are detectable only in certain clinical conditions such as EBV infection, SLE, HIV [1]. Many mAbs derived from the VH4-34 heavy chain gene bind to a distinct straight chain poly n-acetyl lactosamine, referred to as the i/I antigen [2,3] and found on normal fetal red blood cells (RBCs) and mature B cells [4]. On glycan array (Consortium for Functional Glycomics), these VH4-34 encoded antibodies bind a long straight chain, poly N-acetyllactosamine with or without a terminal sialic acid [5]. By using immuno-precipitation and Mass Spectrometry (Nano ESI), our group further identified
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