Chimeric IgG/A Tumor Immunotherapy

嵌合 IgG/A 肿瘤免疫疗法

• 批准号: 8522804
• 负责人: KEITH WYCOFF
• 金额: $ 27.68万
• 依托单位: PLANET BIOTECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8522804
• 关键词: Accounting; Acetylglucosamine; Antibodies; Binding; Breast Cancer Cell; Cancer Patient; Cancer cell line; Cause of Death; Clinical; Clinical Trials; Complement; Development; Diagnosis; ERBB2 gene; Effector Cell; Enhancing Antibodies; FCGR3B gene; Fab domain; Fc Receptor; Fc domain; Fucose; Goals; Half-Life; Human; IgA2; IgG1; Immune; Immunoglobulin A; Immunoglobulin G; Immunotherapy; In Vitro; Life; Light; Link; Malignant Neoplasms; Marketing; Measures; Modeling; Monoclonal Antibodies; NK Cell Activation; Natural Killer Cells; Nicotiana; Pathway interactions; Pennsylvania; Plants; Polysaccharides; Population; Proteins; Recombinant Antibody; Recruitment Activity; Roche brand of trastuzumab; Serum; Structure; System; Therapeutic; Therapeutic Monoclonal Antibodies; Transgenic Mice; Transgenic Organisms; Tumor Antibodies; Universities; Variant; Work; antibody engineering; antibody-dependent cell cytotoxicity; base; cancer therapy; cell type; chimeric antibody; glycosylation; glycosyltransferase; improved; in vivo; killings; malignant breast neoplasm; neonatal Fc receptor; neoplastic cell; neutrophil; novel; public health relevance; receptor; receptor binding; tumor

DESCRIPTION (provided by applicant): Antibody-dependent cellular cytotoxicity (ADCC) is an important mechanism by which therapeutic monoclonal antibodies (mAbs) kill tumor cells. However, killing by current therapeutic IgG mAbs is not optimal. Inefficient ADCC provides a potential escape mechanism for tumors and can be targeted to improve antibody- based cancer therapies. Most of the tumor-directed mAbs used in clinical trials are human IgG1, which can activate complement and/or recruit NK cells for ADCC by binding to Fc¿RIIIa (CD16). Several groups have shown that IgA triggers potent ADCC by binding to the Fc¿RI (CD89) and recruiting neutrophils. Our goal is to create a new class of potent anti-tumor antibodies that can activate a wide variety of immune cell types bearing either the Fc¿RI or Fc?RIIIa. These novel chimeric heavy chains and associated light chains will be expressed in plants to produce antibodies with specific N-glycan structures and enhanced antibody dependent cellular cytotoxicity (ADCC) activity. Structural studies of IgA binding to the Fc?RI and IgG1 binding to the Fc?RIIIa suggest that a chimeric antibody containing both IgG1 and IgA domains, and bound to a tumor cell target, will bind and activate both receptors on immune effector cells. As proof of concept we will link the Fab domains of an anti-HER2 antibody to a fusion of the Fc ?1 CH1-CH2-CH3 domains and Fc ?2 CH2-CH3 domains. IgG1-only and IgA2-only versions will be constructed as controls. The Fc of IgG1 is expected to confer three benefits: (a) prolongation of serum half-life via FcRn binding; (b) purification using Protein A; and (c) augmented cellular recruitment and activation of natural killer (NK) cells via Fc? receptor binding. The IgA2 Fc is expected to confer augmented cellular recruitment and activation of polymorphonuclear cells (PMN) via Fc?RI binding. Recent studies have demonstrated the importance of IgG Fc glycosylation for Fc?R binding and maximizing ADCC. In particular, the absence of core ?1-6)-Fucose and the presence of a bisecting N- acetylglucosamine (GlcNAc) residue each enhance Fc binding to Fc?RIIIa. By co-expressing our recombinant antibodies along with specific glycosyltransferases in a transgenic Nicotiana benthamiana background we will produce antibodies with N-glycan structures that are optimal for participating in ADCC. We will produce six variant antibody forms (IgA, IgG and chimeric IgG/A, each with two different N- glycosylation types), all bearing the same anti-HER-2/neu/c-Erb-B2 Fab region, using our plant expression system and evaluate their ability to direct ADCC in vitro against standard breast cancer cell lines. Our collaborators at the University of Pennsylvania will evaluate the ability of these recombinant antibodies to shrink HER2-expressing syngeneic tumors in transgenic mice expressing both HER2/neu and human Fc?RI.

描述（由申请人提供）：抗体依赖性细胞毒性（ADCC）是治疗性单克隆抗体（mab）杀死肿瘤细胞的重要机制。然而，目前治疗性IgG单抗的杀伤效果并不理想。低效的ADCC为肿瘤提供了一种潜在的逃逸机制，可以靶向改善基于抗体的癌症治疗。临床试验中使用的大多数肿瘤靶向单克隆抗体是人IgG1，它可以通过与Fc¿RIIIa （CD16）结合来激活补体和/或募集NK细胞以治疗ADCC。一些研究小组已经表明，IgA通过与Fc¿RI （CD89）结合并招募中性粒细胞来触发有效的ADCC。我们的目标是创造一种新型的强效抗肿瘤抗体，这种抗体可以激活多种携带Fc¿RI或Fc？RIIIa。这些新的嵌合重链和相关轻链将在植物中表达，产生具有特异性n -聚糖结构的抗体，并增强抗体依赖性细胞毒性（ADCC）活性。