Defining the Role of Affinity in Antibody-Based Tumor Targeting and Penetration

定义亲和力在基于抗体的肿瘤靶向和渗透中的作用

• 批准号: 7759124
• 负责人: GREGORY P ADAMS
• 金额: $ 31.54万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-05 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7759124
• 关键词: Academia; Affect; Affinity; Antibodies; Antibody Affinity; Antibody Degradation; Antigen Targeting; Antigens; Binding; Binding Sites; Biodistribution; Biological Availability; Blood Circulation; Blood Vessels; Caliber; Cell surface; Cells; Clinical; Complement-Dependent Cytotoxicity; Data; Development; Diffuse; ERBB2 gene; Engineering; Epidermal Growth Factor Receptor; Epitopes; Equilibrium; Future; Growth; Human; Immune system; Immunodeficient Mouse; Immunoglobulin Constant Region; Immunoglobulin G; Immunologics; Industry; Lead; Learning; Length; Libraries; Ligand Binding; Ligands; Malignant Neoplasms; Mediating; Microscopic; Monoclonal Antibodies; Mus; Mutate; Names; Normal tissue morphology; Penetration; Phage Display; Play; Positioning Attribute; Process; Property; Public Health; Research; Role; Rosa; SHFM1 gene; Series; Signal Transduction; Solid Neoplasm; Stream; Structure; Surface; System; Testing; Therapeutic; Time; Transgenic Mice; Transgenic Organisms; Translating; Treatment Efficacy; Tumor Antibodies; Tumor Antigens; Ursidae Family; Variant; Work; antibody-dependent cell cytotoxicity; base; cancer therapy; clinically relevant; design; in vivo; insight; killings; mouse model; mutant; neoplastic cell; overexpression; receptor; receptor internalization; tumor

Due to their recent demonstration of efficacy in a number of malignancies, monoclonal antibodies (MAb) are becoming increasingly important in cancer therapy. Most efforts to develop new antibody-based molecules are focused on identifying those with the highest possible affinity for the tumor antigen. Using small, single- chain Fv (scFv) molecules that ranged in affinity for the same epitope of HER2 from 1x10-7 M to 1x10-11 M. We showed that high affinity may impair the ability of an antibody to penetrate into a solid tumor, leading to perivascular localization and potential suboptimal therapeutic efficacy. This work validated a "Binding Site Barrier" hypothesis posed by Weinstein that stated that antibodies of very high affinity would be limited in their ability to penetrate solid tumors. A limitation of our earlier work was that scFv are rapidly eliminated from the circulation, thus limiting the ability to study tumor penetration over time. We have recently generated full-length IgG versions of the scFv molecules described above and are in the position to elucidate the role of affinity in tumor targeting and penetration and determine the mechanisms underlying this process. Preliminary data indicate that high affinity also detracts from tumor targeting and penetration of Ig. The hypotheses underlying this proposal are that 1) IgG molecules with very high affinity for tumor antigen will demonstrate a reduced ability to penetrate into solid tumors, 2) a major mechanism behind the restricted penetration of high affinity antibodies into solid tumors is the internalization and degradation by tumor cells and 3) lower affinity IgG molecules may be superior to higher affinity antibodies in mediating anti-tumor effects. We will evaluate the roles of binding affinity, antigen shedding, antigen/MAb internalization and normal tissue antigen expression on the tumor targeting and tumor penetration of anti-HER2 MAbs. We will also determine if changes in affinity, and the attendant impacts on tumor targeting and penetration, influence the anti-tumor efficacy of unconjugated anti-tumor MAbs, thereby providing information that can help guide future rational development of anti-tumor MAbs. This research is directly relevant to public health, as it will guide the development of new antibodies for the treatment of cancer. Learning how the binding strength (affinity) of an antibody for its target on the tumor cell surface affects the ability of the antibody to move into the tumor and kill tumor cells will allow us to create more effective antibody-based treatments for cancer.

由于最近证明单克隆抗体 (MAb) 对多种恶性肿瘤有效，因此 在癌症治疗中变得越来越重要。最大努力开发新的基于抗体的分子 重点是鉴定那些与肿瘤抗原具有最高可能亲和力的抗原。使用小型、单 对 HER2 相同表位的亲和力范围为 1x10-7 M 至 1x10-11 M 的链 Fv (scFv) 分子。 我们发现高亲和力可能会损害抗体渗透到实体瘤的能力，导致 血管周围定位和潜在的次优治疗效果。这项工作验证了“结合位点 韦恩斯坦提出的“屏障”假说指出，亲和力非常高的抗体将受到限制 他们穿透实体瘤的能力。我们早期工作的一个局限性是 scFv 很快被消除 从循环中排出，从而限制了研究肿瘤随时间渗透的能力。我们最近生成了 上述 scFv 分子的全长 IgG 版本，能够阐明 肿瘤靶向和渗透的亲和力并确定该过程的机制。 初步数据表明，高亲和力也会损害 Ig 的肿瘤靶向和渗透。这 该提议的假设是 1) 对肿瘤抗原具有非常高亲和力的 IgG 分子将 表现出渗透到实体瘤的能力降低，2）限制性背后的主要机制 高亲和力抗体渗透进入实体瘤是肿瘤细胞的内化和降解 3) 较低亲和力的 IgG 分子在介导抗肿瘤方面可能优于较高亲和力的抗体 影响。我们将评估结合亲和力、抗原脱落、抗原/单克隆抗体内化和 正常组织抗原表达对抗 HER2 MAb 的肿瘤靶向和肿瘤渗透的影响。我们将 还确定亲和力的变化以及随之而来的对肿瘤靶向和渗透的影响是否会影响 未结合的抗肿瘤单克隆抗体的抗肿瘤功效，从而提供有助于指导的信息 未来抗肿瘤单克隆抗体的合理开发。这项研究与公共卫生直接相关，因为它将 指导用于治疗癌症的新抗体的开发。了解结合强度如何 抗体对其肿瘤细胞表面靶标的（亲和力）影响抗体进入肿瘤细胞的能力 肿瘤并杀死肿瘤细胞将使我们能够创造出更有效的基于抗体的癌症治疗方法。