Biospecific Antibody Pretargeting for NHL

NHL 生物特异性抗体预靶向

• 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
• 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' 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

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将评估基于双特异性抗体(BsMAb)的预靶向方法治疗非霍奇金淋巴瘤 霍奇金淋巴瘤(NHL)。该项目将从对双特异性抗体的评估开始，该抗体由一个 人源化抗CD20或抗CD22将与新型鼠抗组胺-琥珀酸甘氨酸化学偶联 (HSG)抗体。与分子工程和抗体生产核心合作， 将制备重组抗CD20 bsMAb并进行随后的检测。重组bsMAb有望具有 更有利的药代动力学，但与化学偶联的bsMAb具有同等的结合性能，使它们更 具有吸引力的临床用药。经过改造的bsMAb将专注于测试一种三价bsMAb 与肿瘤靶抗原的二价结合和与HS.G.的单价结合 治疗研究设计，在SCID或携带人类B细胞淋巴瘤异种移植的裸鼠身上将有助于确定 用于优化的特定参数，如bsMAb蛋白质剂量、间隔间距和多肽剂量 此预定位程序，而且由于一个中心假设是预定位将比直接 放射性标记抗体，这些比较将与项目2合作进行。一个二价HSG多肽将 使用具有单一DOTA部分的90Y、Inln和177Lu进行放射性标记。模拟肿瘤模型 将对微转移疾病和已确诊疾病进行检查，以评估这些疾病的最佳放射性核素。 条件，以及与俄歇发射的HL11结合物或与裸露抗体的结合策略。这 该项目还将在体外检查一些不同的策略，这些策略可能被证明有助于鼓励 预靶标肽的内化或促进细胞凋亡，然后可以在体内进行检查。最终， 项目4计划使用重组bsMAb的这种预靶向方法启动一项临床试验，因此 该项目将有助于获得将用于IND的临床前靶向和毒性研究 呈件。