Human Monocolonal Antibodies for CNS Remyelination

描述(申请人提供)：当前研究的主要目标将是选择两种自然产生的人类免疫球蛋白抗体之一的最佳重组形式，这些抗体被证明可以刺激再髓鞘形成，以进一步开发用于炎症性脱髓鞘疾病的临床测试，例如MS。这些抗体被命名为sHIgM22和sHIgM46，由梅奥诊所的Rodriquez实验室通过筛选单克隆性丙种球蛋白病患者的血清库而分离出来。分离、克隆和鉴定这些抗体是第一阶段STTR赠款的特定目标的一部分。这些抗体已被证明能与少突胶质细胞反应，并在SJL/J小鼠的泰勒氏小鼠脑脊髓炎病毒模型中刺激重新髓鞘形成。目前拨款的具体目标将是：将这些抗体的特征扩展到鉴定生物相关的抗原，并进一步阐明抗体刺激重新髓鞘形成的潜在机制。开发一个强大的、可扩展的制造系统，适合生产商业和临床供应的抗体。将抗体的测试扩展到其他炎性中枢神经系统脱髓鞘疾病的模型系统，并评估抗体的毒理学、药代动力学和ADME特性。

DESCRIPTION (provided by applicant): The primary goal of the current research will be to select the best recombinant form of one of two naturally occurring human igM antibodies demonstrated to stimulate remyelination to further develop for clinical testing in inflammatory demyelinating disease, such as MS. These antibodies, designated sHIgM22 and sHIgM46, were isolated by the Rodriquez laboratory at the Mayo Clinic by screening a bank of sera from patients with monoclonal gammopathy. The isolation, cloning and characterization of these antibodies were part of the specific aims of a Phase I STTR grant. The antibodies have been demonstrated to react with oligodendrocytes and to stimulate remyelination in the Theiler's Murine Encephalomyelitis Virus model in the SJL/J mouse. The specific aims of the current grant will be: Extend the characterization of each of these antibodies to the identification of the biologically relevant antigen and further elucidate the underlying mechanism by which the antibodies stimulate remyelination. Develop a robust scaleable manufacturing system that is suitable for producing commercial and clinical supplies of antibody. Extend the testing of the antibodies into other model systems of inflammatory CNS demyelinating disease and assess the toxicologic, pharmacokinetic and ADME properties of the antibodies.