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Development of Novel Immunoconjugates for Application in Cancer Therapeutics

开发用于癌症治疗的新型免疫缀合物

基本信息

批准号：
8032462
负责人：
Douglas Dean Young
金额：
$ 4.12万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8032462
关键词：
4-azidophenylalanine Amino Acids Amino Acyl-tRNA Synthetases Animal Cancer Model Antibodies Apoptosis Architecture Biochemical Biological Availability Bone Marrow Cell Transplantation Cells Chemicals Chemistry Codon Nucleotides Complementary DNA Complex Complex Mixtures Coupled Coupling Cysteine DNA Development Diagnostic Doxorubicin Drug Kinetics Dyes Engineering Enzyme-Linked Immunosorbent Assay Enzymes Evaluation Fab Immunoglobulins Family Generations Genetic Genetic Code Health Hela Cells Human Image Immunoconjugates Immunofluorescence Immunologic Label Laboratories Lead Link Location Lysine Malignant Neoplasms Marketing Medical Metals Methods Microscopy Names Oligonucleotides Organism Paclitaxel Peptides Pharmaceutical Preparations Positioning Attribute Preparation Production Property Proteins Radioactive Radioimmunotherapy Radioisotopes Reaction Research Roche brand of trastuzumab Site Solvents Sorting - Cell Movement Specificity Sulfhydryl Compounds Surface TNF gene TNFRSF10B gene TNFSF10 gene Techniques Technology Therapeutic Therapeutic Agents Therapeutic antibodies Toxic effect Toxin Transfer RNA Tumor Cell Line Western Blotting Y 90 Ibritumomab Tiuxetan amino group antibody conjugate antigen binding cancer cell cancer therapy combat combinatorial cytokine cytotoxic cytotoxicity fluorophore immunogenic in vivo iodine-131-tositumomab link protein mutant novel public health relevance small molecule stem targeted delivery therapeutic protein

项目摘要

DESCRIPTION (provided by applicant): The expansion of the genetic code beyond the 20 canonical amino acids has been exploited to dramatically impact the therapeutic potential of proteins towards a plethora of human health issues. Most notably, the generation of well-defined immunoconjugates (antibodies linked to a variety of chemical entities) can alter the paradigm of cancer treatment, affording an extremely specific and highly regulated mechanism for combating malignant cells. This research aims to employ non-natural amino acids to develop novel techniques for the generation of immunoconjugates, and investigate their therapeutic potential. Currently there are three conjugated therapeutic antibodies on the market; however, specific issues with the bioconjugation reaction are detrimental to the widespread application of therapeutic immunoconjugates. Most immunoconjugates are generated using chemistries relying upon natural amino acid functionalities (e.g. the amino group of lysine), which results in non-specific labeling of the antibody as it possesses multiple residues which can participate in the bioconjugation reaction. Additionally, the residue may not be solvent-exposed or in an optimal location for bioconjugation. These non-specific reactions produce mixtures of immunoconjugates that possess multiple labels in different locations, which may decrease the functionality of the antibody, as well as lead to issues in regulatory approvals. However, employing the Schultz technology, a unique functionality can be incorporated in a specific location in the antibody, affording a bioconjugation reaction that yields a single product. The incorporation of p-acylphenylalanine into the Fab (fragment, antigen binding) region of an antibody can provide a convenient way to rapidly and efficiently generate immunoconjugates. These antibodies can be coupled to a variety of therapeutic agents such as toxins, radioisotopes, or other biomacromolecules. This approach solves all of the previously noted issues with the generation of therapeutic immunoconjugates and represents the next technological advance for the highly specific treatment of a variety of human health issues. PUBLIC HEALTH RELEVANCE: With the expression of the acylphenylalanine antibody mutant, it becomes feasible to couple a variety of therapeutic agents onto the antibody. Specifically, this research intends to investigate the conjugation of therapeutic small molecules and additional proteins to the antibody to afford targeted delivery and more favorable pharmacokinetic properties.

描述(申请人提供)：遗传密码的扩展超出了20种典型氨基酸，已经被利用来极大地影响蛋白质对过多的人类健康问题的治疗潜力。最值得注意的是，定义明确的免疫结合物(与各种化学实体相连的抗体)的产生可以改变癌症治疗的范式，为抗击恶性细胞提供了一种极其特异和高度调控的机制。本研究旨在利用非天然氨基酸开发产生免疫结合物的新技术，并探索其治疗潜力。目前市场上有三种结合的治疗性抗体；然而，生物结合反应的特定问题不利于治疗性免疫结合物的广泛应用。大多数免疫结合物是使用依赖于天然氨基酸功能(例如赖氨酸的氨基)的化学方法产生的，这导致抗体的非特异性标记，因为它具有参与生物结合反应的多个残基。此外，残留物可能不是暴露在溶剂中或处于生物结合的最佳位置。这些非特异性反应会产生免疫结合物的混合物，这些混合物在不同的位置具有多个标记，这可能会降低抗体的功能，并导致监管批准的问题。然而，使用舒尔茨技术，可以在抗体的特定位置加入独特的功能，提供生物结合反应，产生单一产品。将对酰基苯丙氨酸掺入抗体的Fab(片段，抗原结合)区域，可以提供一种快速有效地产生免疫结合物的简便方法。这些抗体可以与各种治疗剂偶联，如毒素、放射性同位素或其他生物大分子。这种方法解决了之前提到的产生治疗性免疫结合物的所有问题，并代表着高度特异地治疗各种人类健康问题的下一步技术进步。公共卫生相关性：随着酰基苯丙氨酸抗体突变体的表达，将各种治疗剂偶联到抗体上成为可能。具体地说，本研究旨在研究治疗性小分子和附加蛋白与抗体的偶联，以提供靶向传递和更有利的药代动力学特性。