Immunotoxins in bone marrow transplantation

骨髓移植中的免疫毒素

基本信息

批准号：
8835057
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 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8835057
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.

描述（由申请人提供）：迫切需要药物难治性B细胞恶性肿瘤的替代疗法。我们使用上一个周期的进步来开发一类新的重组双特异性靶向毒素，具有扩展的能力，可以识别更广泛的B细胞癌。通过这笔赠款的资金，我们发现双特异性靶向毒素可以通过融合两个重复的SCFV亚基制成，从而产生双特异性配体指示毒素，并且它们具有优于单特种靶向毒素的活性。我们将该药物带入白血病临床试验。发现令人鼓舞，但初步数据表明毒素免疫原性将是预期的问题。需要多种剂量才能获得持续的缓解，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的新方法来脱氧蛋白，这可能对将其他分子进行启示具有影响。在AIM 1中，我们建议研究这种脱节。该提案的资金也导致了具有靶向癌症干细胞的能力的完全不同的靶向毒素的发展。当前的理论表明，癌细胞像正常细胞一样分化。癌细胞种群由一小部分分化，自我更新，肿瘤引发干细胞和更大的分化肿瘤细胞的队列组成。较大的分化细胞更容易受到化学疗法的影响，而分化较少的癌症干细胞的较小比例更具耐药性，从而导致癌症药物难治性复发。我们创建了一种针对癌症干细胞的新靶向毒素，并且显然在癌症的全身小鼠模型中具有治疗功效。代理具有与各种不同癌症相对的优势。在AIM 2中，我们建议研究靶向肿瘤干细胞的新策略。 AIM 1与AIM 2有关，因为Deimmunization策略也用于构建具有抗茎细胞的靶向毒素。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Targeting CD133 in an in vivo ovarian cancer model reduces ovarian cancer progression.

DOI：
10.1016/j.ygyno.2013.05.027
发表时间：
2013-09
期刊：
Gynecologic oncology
影响因子：
4.7
作者：
Skubitz AP;Taras EP;Boylan KL;Waldron NN;Oh S;Panoskaltsis-Mortari A;Vallera DA
通讯作者：
Vallera DA

Development of a Deimmunized Bispecific Immunotoxin dDT2219 against B-Cell Malignancies.

DOI：
10.3390/toxins10010032
发表时间：
2018-01-06
期刊：
Toxins
影响因子：
4.2
作者：
Schmohl JU;Todhunter D;Taras E;Bachanova V;Vallera DA
通讯作者：
Vallera DA

A bispecific EpCAM/CD133-targeted toxin is effective against carcinoma.

DOI：
10.1007/s11523-013-0290-9
发表时间：
2014-09
期刊：
Targeted oncology
影响因子：
5.4
作者：
Waldron NN;Barsky SH;Dougherty PR;Vallera DA
通讯作者：
Vallera DA

Molecular modification of a recombinant, bivalent anti-human CD3 immunotoxin (Bic3) results in reduced in vivo toxicity in mice.

DOI：
10.1016/j.leukres.2004.08.006
发表时间：
2005-03
期刊：
Leukemia research
影响因子：
2.7
作者：
D. Vallera;D. Todhunter;D. Kuroki;Y. Shu;A. Sicheneder;A. Panoskaltsis‐Mortari;Vincent D. Vallera;
通讯作者：
D. Vallera;D. Todhunter;D. Kuroki;Y. Shu;A. Sicheneder;A. Panoskaltsis‐Mortari;Vincent D. Vallera;

Radiotherapy of CD45-expressing Daudi tumors in nude mice with yttrium-90-labeled, PEGylated anti-CD45 antibody.

使用钇 90 标记的聚乙二醇化抗 CD45 抗体对裸鼠中表达 CD45 的 Daudi 肿瘤进行放射治疗。

DOI：
10.1089/cbr.2007.366
发表时间：
2007
期刊：
Cancer biotherapy & radiopharmaceuticals
影响因子：
3.4
作者：
Vallera,DanielA;Sicheneder,AndyR;Taras,ElizabethP;Brechbiel,MartinW;Vallera,JesseA;Panoskaltsis-Mortari,Angela;Burns,LindaJ
通讯作者：
Burns,LindaJ