Immunotoxins in bone marrow transplantation

骨髓移植中的免疫毒素

基本信息

批准号：
8181596
负责人：
Daniel A Vallera
金额：
$ 23.85万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
1984
资助国家：
美国
起止时间：
1984-01-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8181596
关键词：
Address Affinity Alternative Therapies Amino Acids Animals Antibodies Antibody Formation Avidity B lymphoid malignancy B-Cell Acute Lymphoblastic Leukemia B-Cell Lymphomas B-Lymphocytes Binding Biological Biological Assay Biomedical Engineering Bone Marrow Transplantation CD19 gene CD22 gene Cancer cell line Cells Clinical Trials Cyclic GMP Data Development Diphtheria Toxin Disease Disease remission Dose Drug Kinetics Drug resistance Epitope Mapping Epitopes Exotoxins Flow Cytometry Funding Future Goals Grant Head and Neck Cancer Hot Spot Human Hybridomas Immunization Immunotoxins In Vitro In complete remission Injection of therapeutic agent Institution Ligands Literature Mainstreaming Malignant Epithelial Cell Malignant Neoplasms Measures Microarray Analysis Minor Mutagenesis Mutate Mutation Normal Cell Nude Mice Patients Pharmaceutical Preparations Phase I Clinical Trials Population Procedures Pseudomonas Recombinants Recording of previous events Refractory Relapse Reporting Research Safety Sorting - Cell Movement Stem cells Survivors Targeted Toxins Testing Therapeutic Time Toxin Treatment Efficacy Tumor Stem Cells Work base cancer cell cancer stem cell chemotherapy cohort complementarity-determining region 3 drug efficacy immunogenic immunogenicity in vitro Assay in vivo leukemia malignant breast neoplasm mouse model neoplastic cell operation response self-renewal theories tool tumor tumor initiation

项目摘要

DESCRIPTION (provided by applicant): Alternative therapies for drug refractory B cell malignancies are urgently needed. We used advances last cycle to develop a new class of recombinant bispecific targeted toxin with expanded ability to recognize a wider range of B cell cancers. With funding from this grant, we discovered that bispecific targeted toxins could be made by fusing two repeating scFv subunits creating a bispecific ligand directed toxin and they had superior activity over monospecific targeted toxins. We brought the drug to clinical trial for leukemia. Findings are encouraging, but preliminary data indicates that toxin immunogenicity will be a problem as anticipated. Multiple dosing is required to obtain sustained remissions and this generates anti-toxin antibodies that impact drug efficacy. To this end, we have found an important new and successful way to deimmunize our toxin that may have implications for deimmunizing other molecules. In aim 1, we propose to study this deimmunization. Funding from this proposal has also led to the development of a very different targeted toxin that has the ability to target cancer stem cells. Current theory dictates that cancer cells differentiate as do normal cells. The cancer cell population consists of a small cohort of less differentiated, self renewing, tumor initiating stem cells and a larger cohort of more differentiated tumor cells. More differentiated cells are more susceptible to chemotherapy and the minor fraction of less differentiated cancer stem cells are more drug resistant, thus contributing to drug refractory relapse in cancer. We have created a new targeted toxin that targets cancer stem cells and clearly has therapeutic efficacy in systemic mouse models of cancer. The agent has the advantage of working against a variety of different cancers. In aim 2, we propose to study this new strategy of targeting tumor stem cells. Aim 1 relates to Aim 2 since the deimmunization strategies are used to construct anti-stem cell targeted toxins as well. PUBLIC HEALTH RELEVANCE: Our group has discovered a new class of biological drugs called bispecific targeted toxins that show superiority over their monospecific counterparts and can be genetically modified to address some of the major problems in the field and we have proven that multiple treatments with these drugs are highly effective against systemic cancer in animals resulting in long-term disease free survivors. In this proposal, we will be addressing some of the major issues with these drugs. We will be investigating improvements in reducing their immunogenicity and destroying the most important drug resistant cells, cancer stem cells.

描述（由申请人提供）：迫切需要针对药物难治性 B 细胞恶性肿瘤的替代疗法。我们利用上个周期的进展开发了一类新型重组双特异性靶向毒素，具有识别更广泛 B 细胞癌症的能力。借助这笔资金的资助，我们发现可以通过融合两个重复的 scFv 亚基来制造双特异性靶向毒素，从而产生双特异性配体定向毒素，并且它们比单特异性靶向毒素具有更好的活性。我们将该药物用于白血病的临床试验。研究结果令人鼓舞，但初步数据表明毒素免疫原性将成为预期的问题。需要多次给药才能获得持续缓解，这会产生影响药物疗效的抗毒素抗体。为此，我们找到了一种重要的新且成功的方法来消除我们的毒素的免疫，这可能对消除其他分子的免疫产生影响。在目标 1 中，我们建议研究这种去免疫化。该提案的资助还导致了一种非常不同的靶向毒素的开发，该毒素能够靶向癌症干细胞。目前的理论表明癌细胞和正常细胞一样分化。癌细胞群由一小群分化程度较低、自我更新的肿瘤起始干细胞和一大群分化程度较高的肿瘤细胞组成。分化程度较高的细胞对化疗更敏感，而一小部分分化程度较低的癌症干细胞的耐药性更强，从而导致癌症的药物难治性复发。我们创造了一种新的靶向毒素，该毒素针对癌症干细胞，并且在全身性小鼠癌症模型中具有明显的治疗功效。该药物的优点是可以对抗多种不同的癌症。在目标 2 中，我们建议研究这种针对肿瘤干细胞的新策略。目标 1 与目标 2 相关，因为去免疫策略也用于构建抗干细胞靶向毒素。公共卫生相关性：我们的小组发现了一种称为双特异性靶向毒素的新型生物药物，它比单特异性同类药物具有优越性，并且可以进行基因改造以解决该领域的一些主要问题，并且我们已经证明使用这些药物进行多种治疗对动物全身性癌症非常有效，可导致长期无病生存。在本提案中，我们将解决这些药物的一些主要问题。我们将研究降低其免疫原性并破坏最重要的耐药细胞（癌症干细胞）的改进方法。