Tetravalent antibodies with altered FcRn binding sites

FcRn 结合位点改变的四价抗体

• 批准号: 7142456
• 负责人: JOAN E. SMALLSHAW
• 金额: $ 17.9万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7142456
• 关键词: antibody; binding sites; neoplasm /cancer

DESCRIPTION (provided by applicant): Many tumor-reactive monoclonal antibodies have been developed but most have little anti-tumor activity. Often this can be overcome by using multimeric forms of the antibody which are then able to induce death signals in the cell by hypercrosslinking their target antigen. In addition, increasing their in vivo half-life to maximize tumor penetration is often helpful. Although chemically-generated tetravalent antibodies are highly effective in vitro, they have poor pharmacokinetics due to their large size. They are also difficult and expensive to produce and consist of heterogeneous mixtures of products. Recombinant multivalent constructs comprised of several Fv fragments have no effector functions and short half lives in vivo. With regard to the Fc region of an antibody, binding to FcRns in endothelial cells is critical for prolonging their in vivo half life. Hence, specific mutations in the Fc region of an IgG can increase or decrease FcRn binding and thereby increase or decrease its serum half-life. The goal of this study is to construct a panel of antibodies that 1) are tetravalent and contain a human Fc region in order to enhance their ability to induce apoptosis and to decrease immunogenicity, 2) have sizes comparable to IgGs for good tumor penetration, and 3) incorporate FcRn-mutations, to alter their half life in vivo. Constructs with both longer and shorter half-lives will be evaluated in vitro and in vivo in mice with human tumors. The former will be used as "naked" antibodies where a long half-life should be advantageous. The latter will be used as immunotoxins, where a short half-life may reduce toxic side effects, thereby increasing the maximum tolerated dose.

描述（由申请人提供）：已经开发了许多肿瘤反应性单克隆抗体，但大多数抗肿瘤活性很低。通常，这可以通过使用多聚体形式的抗体来克服，所述抗体然后能够通过使其靶抗原超交联而在细胞中诱导死亡信号。此外，增加它们的体内半衰期以最大化肿瘤渗透通常是有帮助的。尽管化学产生的四价抗体在体外是高度有效的，但由于它们的大尺寸，它们具有差的药代动力学。它们的生产也是困难和昂贵的，并且由产品的异质混合物组成。由几个Fv片段组成的重组多价构建体在体内没有效应子功能并且半衰期短。关于抗体的Fc区，与内皮细胞中的FcRn结合对于延长其体内半衰期至关重要。因此，IgG的Fc区中的特异性突变可以增加或减少FcRn结合，从而增加或减少其血清半衰期。本研究的目的是构建一组抗体，1）为四价并含有人Fc区，以增强其诱导细胞凋亡和降低免疫原性的能力，2）具有与IgG相当的大小，以实现良好的肿瘤穿透，3）掺入FcRn突变，以改变其体内半衰期。具有较长和较短半衰期的构建体将在具有人肿瘤的小鼠中进行体外和体内评估。前者将用作“裸”抗体，其中长半衰期应该是有利的。后者将被用作免疫毒素，其中短的半衰期可以减少毒副作用，从而增加最大耐受剂量。