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Generation of antibody-drug conjugates by proximity-based sortase-mediated ligation

通过基于邻近的分选酶介导的连接生成抗体-药物缀合物

基本信息

批准号：
10437944
负责人：
Feifan Yu
金额：
$ 61.1万
依托单位：
ALPHATHERA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10437944
关键词：
Adult Amino Acid Sequence Antibodies Antibody Avidity Antibody Formation Antibody Specificity Antibody-drug conjugates Binding Biodistribution Biological Assay Blood Circulation C-terminal Chemicals Chemistry Clinical Comparative Pathology Cysteine Data Development Disulfides Drug Industry Drug Kinetics Drug Stability Effectiveness Engineering Enzymes Exposure to FDA approved Formulation Generations Goals Human Hydrophobicity IgG Receptors IgG1 Immunocompetent Immunoglobulin G In Vitro Intravenous Label Lead Ligation Location Lysine Malignant Neoplasms Malignant neoplasm of pancreas Measurable Mediating Methods Modality Modeling Modification Molecular Movement Mus Outcome Pennsylvania Peptides Pharmaceutical Preparations Polysaccharides Preclinical Testing Preparation Property Proteins Serum Site Solubility Technology Testing Therapeutic Time Tissues Toxic effect Transglutaminases Universities Variant Vertebral column antibody engineering antitumor drug base cancer therapy chemotherapy clinical translation cytotoxic cytotoxicity effective therapy enzyme activity experience flexibility formylglycine glycosylated IgG interest lead candidate neonatal Fc receptor neoplastic cell novel strategies novel therapeutics pancreatic cancer model pancreatic cancer patients selective expression sortase targeted treatment tumor unnatural amino acids

项目摘要

There has been growing interest in the use of antibody drug conjugates (ADCs) for the treatment of cancer as mounting data suggests an increase in anti-tumor effectiveness and reduced toxicity, compared with the administration of unlabeled antibodies in combination with chemotherapy. Recent evidence has shown that differentially labeled antibodies, i.e. labeled at different locations and with different numbers, can have distinct therapeutic and pharmacokinetic properties and some subpopulations can show little, if any, therapeutic activity yet account for most of the toxicity. Therefore, there has been a movement towards the development of site- specific ADCs, which are precisely labeled with drugs at pre-defined locations. We have recently developed two new approaches for the preparation of highly uniform ADCs, one site-specific bioconjugation approach, Proximity-Based Sortase-mediated protein Ligation (PBS-PL), whereby sortase is used to ligate drugs to a peptide tag that has been introduced into the antibody backbone, and one region- specific bioconjugation approach, Proximity-based Sortase Isopeptide Ligation (PBS-IL), which allows for the labeling of native antibodies with reduced variability compared with current lysine/cysteine residue labeling approaches. Both methods produce ADCs in high yields, are compatible with glycosylated IgG, and offer unlimited flexibility in antibody-drug linker chemistry. Therefore, we believe that these technologies will provide new, favorable approaches for the production of ADCs that will be of interest to the pharmaceutical industry. In this proposal, we have partnered with Integral Molecular and the University of Pennsylvania to develop ADCs against claudin-18 (CLDN 18.2). CLD18.2 is ectopically expressed in several cancers including pancreatic cancer, which is the focus of this proposal. Outcomes for pancreatic cancer patients are poor with a 5-year survival of <8% due to a lack of effective treatment modalities. Therefore, the development of new therapies are a clinical necessity. The highly selective expression of CLDN18.2 in cancer, with no detectable expression on any healthy adult tissues that are accessible to antibodies, make it an attractive option for targeted therapy. We will prepare various ADCs using PBS-PL and PBS-IL and will identify the conjugation approach and ADC formulation that is expected to be most favorable for clinical translation, based on serum stability, pharmacokinetics, and efficacy. Pre-clinical testing will be performed in an orthotopic pancreatic tumor model in syngeneic mice. The specific aims for the proposal are: Aim 1: Produce and characterize anti- CLDN18.2-vcMMAE ADCs using PBS-PL and PBS-IL; Aim 2: Evaluate the binding and efficacy of anti- CLDN18.2-vcMMAE ADCs in vitro; Aim 3. Determine the pharmacokinetics and efficacy of anti-CLDN18.2 ADCs in a murine tumor model

抗体药物偶联物（adc）在癌症治疗中的应用越来越受到关注