Single-chain antibody countermeasures for the Radiation GI Syndrome

放射胃肠道综合症的单链抗体对策

基本信息

批准号：
8646044
负责人：
Jim Rotolo
金额：
$ 30万
依托单位：
CERAMIDE THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8646044
关键词：
Acute Affinity Animal Model Animals Antibodies Apoptosis Atherosclerosis Attenuated Autoimmune encephalitis Binding Biological Assay Biological Availability Bioshield Biotechnology Blood Circulation Blood Vessels Bone Marrow Cell Death Cell Survival Ceramide Signaling Pathway Ceramides Cessation of life Chimeric Proteins Cloning Consensus Sequence Cytoprotection Cytotoxic T-Lymphocytes Data Development Diabetes Mellitus Digestion Directed Molecular Evolution Disasters Dose Drug Kinetics Enzyme-Linked Immunosorbent Assay Epithelial Exposure to Fab Immunoglobulins Gastrointestinal tract structure Genetic Half-Life Hour Human Image Immunofluorescence Immunologic Immunoglobulin Fragments Immunoglobulin G Immunotherapeutic agent In Vitro Inhibition of Apoptosis Intestines Jurkat Cells Lead Length Light Mediating Medical Membrane Modeling Monoclonal Antibodies Mus Nuclear Parents Pathology Penetration Proteins Publishing Radiation Radiation Protection Radiation Syndromes Radiation Tolerance Radiation Toxicity Radioprotection Reagent Recombinants Role Route Schedule Serum Stem cells Syndrome Techniques Testing Therapeutic Therapeutic antibodies Time Tissues Toxic effect Vascular Endothelium Whole-Body Irradiation antibody inhibitor antigen binding base complementarity-determining region 3 cost gastrointestinal graft vs host disease humanized monoclonal antibodies improved in vivo irradiation novel pre-clinical product development prophylactic public health relevance research study small molecule

项目摘要

DESCRIPTION (provided by applicant): Genetic or pharmacologic inhibition of ceramide-mediated cell death within the vascular endothelium of the gastrointestinal tract (GI) protects mice from death from the Radiation GI Syndrome (RGS). Prophylactic administration of anti-ceramide antibody attenuates endothelial apoptosis, resulting in significant protection of intestinal stem cells and animal survival following lethal radiation exposure. Administration 24 h post radiation exposure similarly protects crypt stem cells and dramatically improves survival, indicating that anti-ceramide antibody represents the first effective antibody of small molecule mitigator of lethal RGS. To improve upon the efficacy of anti-ceramide antibody, we propose to select a recombinant single-chain antibody fusion protein containing the known ceramide-binding regions of anti-ceramide antibody as a novel Medical Radiation Countermeasure. Single-chain antibody fusion proteins are smaller derivatives of full length antibodies, and thus offer the advantage of rapid entering into the bloodstream and increased penetration into tissue compared to full-length antibodies. Additionally, single-chain antibody fusion proteins can be modified by general cloning techniques to display preferred target binding, and from a product development standpoint these fusion proteins can be produced easily and at minimal cost. While in some cases single-chain antibody fusion proteins may not retain full activity of the parent antibody, our preliminary data indicates that similar antibody fragments derived by enzymatic digestion of humanized anti-ceramide antibody results in significant protection and mitigation of radiation-induced crypt stem cell lethality, even 24 h after high single-dose exposure. These data indicate that a single-chain antibody fusion protein can be sufficient to induce therapeutic neutralization of ceramide. As such, a neutralizing anti-ceramide single-chain antibody fusion protein represents a promising candidate to fulfill the Project BioShield mandate for development of countermeasures to mitigate acute radiation syndromes within the first 24 h after a nuclear disaster.

描述（由申请人提供）：遗传学或药物抑制神经酰胺介导的细胞死亡，胃肠道血管内皮（GI）（GI）可保护小鼠免受辐射GI综合征（RGS）的死亡。预防性给药抗神经酰胺抗体减弱内皮细胞凋亡，从而在致命辐射暴露后对肠道干细胞和动物存活产生显着保护。辐射暴露后24小时类似地保护隐窝干细胞并大大提高生存率，这表明抗陶瓷抗体代表了致命RGS小分子缓解剂的第一种有效抗体。为了提高抗神经酰胺抗体的功效，我们建议选择一种重组单链抗体融合蛋白，该蛋白含有抗神经酰胺抗体的已知神经酰胺结合区作为一种新型的医疗辐射应对。单链抗体融合蛋白是全长抗体的较小衍生物，因此与全长抗体相比，快速进入血液并渗透到组织中的优势增加。此外，可以通过一般克隆技术来修改单链抗体融合蛋白以显示首选的靶联结，并且从产品开发的角度来看，这些融合蛋白可以轻松地以最低的成本生产。虽然在某些情况下，单链抗体融合蛋白可能无法保留父抗体的全部活性，但我们的初步数据表明，通过酶促消化的人性化抗神经酰胺抗体而得出的类似抗体片段会导致显着保护和缓解辐射诱导的隐秘干细胞lethality，即使在高剂量曝光后，也会导致高度抗体。这些数据表明，单链抗体融合蛋白足以诱导神经酰胺的治疗性中和。因此，中和抗神经酰胺单链抗体融合蛋白代表了履行Bioshield项目授权的有希望的候选人，以开发对核灾难后最初24小时内减轻急性辐射综合症的对策。