Biospecific Antibody Pretargeting for NHL

NHL 生物特异性抗体预靶向

基本信息

批准号：
7728846
负责人：
Robert M Sharkey
金额：
$ 10.06万
依托单位：
CTR FOR MOLECULAR MEDICINE/IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7728846
关键词：
90Y Animals Antibodies Antibody Formation Antigen Targeting Antihistamines Apoptosis Autoradiography B lymphoid malignancy B-Cell Lymphomas Binding Biodistribution Biotin Bispecific Antibodies Cancer Model Cell surface Cells Clinical Clinical Research Clinical Trials Collaborations Colon Carcinoma Colorectal Cancer Complex Condition Coupled Data Development Disease Dose Drug Kinetics Engineering Evaluation Glycine Gold Histamine Human Immunoglobulin G In Vitro Label Localized MS4A1 gene Methods Microscopic Modeling Molecular Monoclonal Antibodies Mus Non-Hodgkin&apos s Lymphoma Nude Mice Numbers Peptides Procedures Property Proteins Radioimmunoconjugate Radioisotopes Radiolabeled Rate Recombinants Research Design SCID Mice Standards of Weights and Measures Streptavidin Surface System Testing Toxic effect Treatment Efficacy Tumor Antigens United States Food and Drug Administration Work Xenograft procedure Y 90 Ibritumomab Tiuxetan base cancer therapy crosslink immunogenic improved in vivo iodine-131-tositumomab killings mouse model novel pre-clinical radiotracer response tumor uptake

项目摘要

Project 1 will evaluate pretargeting approaches based on bispecific antibodies (bsMAb) for the treatment of non- Hodgkin's lymphoma (NHL). The project will start with an evaluation of bispecific antibodies composed of a humanized anti-CD20 or an anti-CD22 that will be chemically coupled with a novel murine anti-histamine-succinylglycine (HSG) antibody. Working in collaboration with the Molecular Engineering and Antibody Production Core, recombinant anti-CD20 bsMAb will be prepared and subsequently tested. Recombinant bsMAb are expected to have more favorable pharmacokinetics yet equal binding properties as the chemically coupled bsMAb, making them more attractive agents for clinical use. The engineered bsMAbs will focus on the testing of a trivalent bsMAb that has divalent binding to the tumor target antigen with monovalent binding to HS.G. In vivo testing, biodistribution and therapy study designs, in SCID or nude mice bearing a human B-cell lymphoma xenograft will aid in determining specific parameters, such as bsMAb protein dose, interval spacing, and peptide dose that should be used to optimize this pretargeting procedure, and since a central hypothesis is that pretargeting will have advantages over a directly radiolabeled antibody, these comparisons will be made in collaboration with Project 2. A divalent HSG peptide will be used that has a single DOTA moiety forradiolabeling with 90Y, inln, and 177Lu. Tumor models mimicking micrometastatic disease and established disease will be examined to assess the optimal radionuclide for these conditions, as well as combination strategies with Auger-emitting^hLLl conjugates or with naked antibodies. This project will also examine a number of different strategies in vitro that might prove useful for encouraging the internalization of the pretargeted peptide or enhancing apoptosis, which may then be examined in vivo. Ultimately, Project 4 plans to initiate a clinical trial using this pretargeting approach with the recombinant bsMAb, and therefore this project will be instrumental in obtaining preclinical targeting and toxicity studies that will be used for the IND submission.

项目1将根据双特异性抗体（BSMAB）评估预先定位的方法，以治疗非 - 霍奇金的淋巴瘤（NHL）。该项目将从对由A组成的双特异性抗体进行评估开始人源化抗CD20或抗CD22将与新型鼠抗抗药性 - 核酸甘氨酸化学结合（HSG）抗体。与分子工程和抗体生产核心合作，重组抗CD20 BSMAB将准备并随后进行测试。重组BSMAB有望具有更有利的药代动力学，但与化学耦合BSMAB相等的结合特性，使其更加临床使用的有吸引力的代理。工程的BSMAB将重点介绍具有三价BSMAB的测试与肿瘤靶抗原的二价结合具有与HS.G的单价结合。体内测试，生物分布和治疗研究设计，在带有人B细胞淋巴瘤异种移植的SCID或裸鼠中，将有助于确定特定参数，例如BSMAB蛋白剂量，间隔间距和肽剂量，应用于优化这种有预定的程序，并且由于中心假设是有限的，而不是直接具有优势放射标记的抗体，这些比较将与项目2合作进行。使用具有90年，INL和177LU的单个dota部分forradiolabeling。肿瘤模型模仿将检查微转移性疾病和已建立的疾病，以评估这些疾病的最佳放射性核素条件以及与螺旋螺旋发射^hlll共轭物或裸抗体的组合策略。这项目还将检查体外的许多不同策略，这些策略可能对鼓励预先靶化肽或增强凋亡的内在化，然后可以在体内检查。最终，项目4计划使用重组BSMAB使用这种有预先的方法来启动临床试验，因此该项目将有助于获取将用于IND的临床前靶向和毒性研究提交。