An Anti-CD-74 MAb-drug Conjugate for B-Cell Malignancies

用于治疗 B 细胞恶性肿瘤的抗 CD-74 MAb 药物偶联物

• 批准号: 6989617
• 负责人: PUJA SAPRA
• 金额: $ 13.43万
• 依托单位: IMMUNOMEDICS, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6989617
• 关键词: B cell lymphoma; B lymphocyte; CD antigens; SCID mouse; antineoplastic antibiotics; disease /disorder model; dosage; doxorubicin; drug adverse effect; drug screening /evaluation; histopathology; immunoconjugates; indium; monoclonal antibody; multiple myeloma; neoplasm /cancer immunotherapy; neoplasm /cancer pharmacology; nonhuman therapy evaluation; pharmacokinetics; radiotracer; therapy design /development; tumor antigens; xenotransplantation

DESCRIPTION (provided by applicant): The objective of this work is to develop an antibody-drug conjugate that will be useful against B-cell malignancies that express the CD74 antigen. More specifically, the conjugate will be a doxorubicin derivative attached to the complementarity-determining region-grafted (humanized) monoclonal antibody termed hLL1. The agent in this project will be developed for the multiple myeloma indication, but the same agent would be expected to be useful against any CD-74-expressing malignancy, including non-Hodgkin's lymphoma (NHL). This SBIR Phase I application will continue to explore the efficacy of the doxorubicin-hLL1 conjugate in a preclinical animal model of human multiple myeloma, since a preliminary indication of efficacy has now already been demonstrated. We expect to see significant efficacy at low doses of administered conjugate, and, hopefully, cures of animals at higher and/or multiple doses. With continuing positive efficacy data, the production of the conjugate will be scaled up to multi-grams of material. In vitro cell binding studies will be done to show that drug conjugation has not impinged antibody-antigen binding characteristics. Studies of the biodistributions of doxorubicin and hLL1 from the conjugate will be carried out, using mass spectrometry and radiolabeled antibody, respectively, to show that localization is antibody specific and cellular antibody uptake can be correlated with cellular anthracycline uptake. In this Phase I SBIR work, feasibility will be shown by a quantifiable demonstration of in vivo efficacy, and the therapeutic index of dox-hlL1 will be determined at both single and multiple weekly doses. With Promising data, SBIR Phase II will support the efforts to transfer the MAb-drug conjugate to a Phase I or Phase I/II clinical trial in multiple myeloma or, in another B-cell malignnacy such as NHL. Positive results in such a Phase I or Phase I/II clinical trial will lead to pivotal studies directed toward securing an FDA-approved antibody-drug conjugate for the selected disease indication.

描述（由申请人提供）：这项工作的目的是开发一种抗体 - 药物结合物，该抗体与表达CD74抗原的B细胞恶性肿瘤有用。更具体地说，偶联物将是附着在互补性区域接枝的（人源化）单克隆抗体中的阿霉素衍生物，称为HLL1。该项目中的药物将用于多发性骨髓瘤指示，但预计将对任何表达CD-74的恶性肿瘤（包括非霍奇金淋巴瘤（NHL））有用。该SBIR I期应用将继续探索阿霉素-HLL1偶联物在人类多发性骨髓瘤的临床前动物模型中的功效，因为现在已经证明了功效的初步指示。我们期望在低剂量的施用结合物中看到明显的疗效，并希望在较高和/或多种剂量的情况下治愈动物。通过持续的积极疗效数据，结合物的产生将扩展到材料的多克。将进行体外细胞结合研究，以表明药物的结合并未影响抗体 - 抗原结合特征。分别使用质谱和放射性标记抗体对偶联物中的阿霉素和HLL1的生物分布进行研究，以表明定位是抗体特异性和细胞抗体摄取的摄取，可以与细胞Anthracharyclacyclaceclaceclaceclaceclaceclace摄取相关。在此阶段I SBIR的工作中，可行性将通过体内功效的可量化证明显示，并且DOX-HLL1的治疗指数将在单个和多个每周剂量下确定。有了有希望的数据，SBIR II期将支持将MAB-Prug偶联物转移到多发性骨髓瘤或其他B细胞恶性肿瘤（例如NHL）中的I或I/II期临床试验的努力。在此类I期或I/II期临床试验中，积极的结果将导致旨在确保FDA批准的抗体 - 药物 - 药物结合物的关键研究。