Abstract
BackgroundPlatelet glycoprotein Ibα (GPIbα) extracellular domain, which is part of the receptor complex GPIb-IX-V, plays an important role in tumor metastasis. However, the mechanism through which GPIbα participates in the metastatic process remains unclear. In addition, potential bleeding complication remains an obstacle for the clinical use of anti-platelet agents in cancer therapy.MethodsWe established a series of screening models and obtained rat anti-mouse GPIbα monoclonal antibodies (mAb) 1D12 and 2B4 that demonstrated potential value in suppressing cancer metastasis. To validate our findings, we further obtained mouse anti-human GPIbα monoclonal antibody YQ3 through the same approach.Results1D12 and 2B4 affected the von Willebrand factor (vWF)-GPIbα interaction via binding to GPIbα aa 41-50 and aa 277-290 respectively, which markedly inhibited the interaction among platelets, tumor cells, and endothelial cells in vitro, and reduced the mean number of surface nodules in the experimental and spontaneous metastasis models in vivo. As expected, YQ3 inhibited lung cancer adhesion and demonstrated similar value in metastasis. More importantly, for all three mAbs in our study, none of their Fabs induced thrombocytopenia.ConclusionOur results therefore supported the hypothesis that GPIbα contributes to tumor metastasis and suggested potential value of using anti-GPIbα mAb to suppress cancer metastasis.
Highlights
Platelet glycoprotein Ibα (GPIbα) extracellular domain, which is part of the receptor complex GPIb-IX-V, plays an important role in tumor metastasis
Qi et al Journal of Hematology & Oncology (2018) 11:117 antibodies may lead to severe bleeding complications [11], which is the main reason to limit the clinical use of these anti-GPIIb-IIIa agents in cancer therapy, the anti-metastatic agent anti-GPIIIa49-66 scFv Ab A11 that has a slight effect on platelet count and vein bleeding time was found to have therapeutic potential in metastasis [7, 12]
Generation and screening of monoclonal antibodies (mAb) targeting mouse platelet GPIbα To generate antibodies that bind to mouse platelet GPIbα, washed mouse platelet lysate was used as the antigen for rat immunization
Summary
Platelet glycoprotein Ibα (GPIbα) extracellular domain, which is part of the receptor complex GPIb-IX-V, plays an important role in tumor metastasis. Two important platelet membrane receptors, glycoprotein Ib-IX-V (GPIb-IX-V) and glycoprotein IIb-IIIa (GPIIb-IIIa, known as integrin αIIbβ3), are essential for tumor cell-platelet adhesion and aggregation when tumor cells invade into vasculature [2]. Qi et al Journal of Hematology & Oncology (2018) 11:117 antibodies may lead to severe bleeding complications [11], which is the main reason to limit the clinical use of these anti-GPIIb-IIIa agents in cancer therapy, the anti-metastatic agent anti-GPIIIa49-66 scFv Ab A11 that has a slight effect on platelet count and vein bleeding time was found to have therapeutic potential in metastasis [7, 12]. While the mechanism of GPIIb-IIIa involvement in tumor metastasis is largely clarified, the role of another important adhesion receptor GPIb-IX-V in metastasis remains debatable [13]. We evaluated the role of GPIb-IX-V and its therapeutic potential in metastasis
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