Translational Multimodality " Antibody" Therapy

转化多模式“抗体”疗法

• 批准号: 6878575
• 负责人: GERALD L DENARDO
• 金额: $ 223.25万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-09 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6878575
• 关键词: immunologic substance development /preparation; neoplasm /cancer radioimmunotherapy; therapy design /development

DESCRIPTION (provided by applicant): The hypothesis for the competitive renewal of the grant, Translational Multimodality "Antibody" Therapy, is that the therapeutic index for radioisotopic molecular targeted radiotherapy (RMTR) can be dramatically improved using novel small molecules and delivery strategies. RMTR has expanded the usefulness of radiation to treat widespread cancer, and small radioisotope carrier molecules can achieve therapeutic indices 10-100X better than that currently achieved using macromolecular MAb carriers. This program has renewed its emphasis on translational research to apply novel science and resources for the development of drugs and strategies to be evaluated in preclinical studies (before transfer to patients). Although the proposals are potentially applicable to most cancers, the focus will be on lymphomas and prostate cancer because of the need for novel treatment and substantial progress achieved using conventional radioimmunotherapy. Using insights from our experience with Lym-1-MAb and HLA-DR targeting, and a combination of unusual capabilities, we have generated synthetic, high affinity (linked) ligands (SHALs) in the first project that selectively bind to unique sites on the beta subunit of HLA-DR, a protein shown to be relatively specific for the malignant lymphocytes of B-lymphomas and leukemias. These novel molecules have been shown to bind selectively to HLA-DR10 and human lymphoma cells and will be used as radioisotopic carriers for systemic radiotherapy. In the second project, novel bispecific, multivalent single-chain MAbs, against the tandem repeat of the mucin protein characteristic of adenocarcinomas and against the DOTA chelator for radiometals, have been generated and placed on a PEGylated scaffold for use in a pretargeting RIT strategy for prostate cancer. Multivalent DOTA will be used as the radiometal carrier. PEGylated bivalent scFvs that bind selectively to prostate cancer have been synthesized. In the third project, the inventor of the "one bead, one peptide" combinatorial libraries has generated serine protease (Activase(R), TNKase(R) biodegradable linkers, stable in plasma, to reduce radiation doses to all normal tissues by eliminating radioisotope carriers from the blood "on demand". In the past, we showed that cathepsin-degradable peptides in radiometal-labeled MAbs reduced hepatic radiation dose. The proposed strategy decreases radiation dose to all normal tissues and is applicable to other radioisotopic targeting systems, both in development and approved, and as a clearance vehicle for pregargeting strategies. Four cores support the projects. Dramatic progress has been made and the likelihood of success is certain.

描述（由申请人提供）：赠款的竞争更新的假设，翻译多模式“抗体”疗法是，可以使用新颖的小分子和递送策略来大大改善放射性分子靶向放射治疗（RMTR）的治疗指数。 RMTR扩大了辐射以治疗广泛癌症的实用性，而小的放射性同位素载体分子可以比使用大分子分子MAB载体更好地实现10-100X的治疗指数。该计划重新强调了转化研究，将新颖的科学和资源应用于临床前研究（转移给患者之前）的药物和策略的发展。 尽管这些建议可能适用于大多数癌症，但由于需要使用常规的放射免疫疗法取得的新治疗和实质性进展，因此重点将放在淋巴瘤和前列腺癌上。 Using insights from our experience with Lym-1-MAb and HLA-DR targeting, and a combination of unusual capabilities, we have generated synthetic, high affinity (linked) ligands (SHALs) in the first project that selectively bind to unique sites on the beta subunit of HLA-DR, a protein shown to be relatively specific for the malignant lymphocytes of B-lymphomas and leukemias. 这些新型分子已被证明可以选择性地与HLA-DR10和人淋巴瘤细胞结合，并将用作全身放射疗法的放射性病载体。 在第二个项目中，已经生成并将其放置在pegyated caffold上，用于在预先构成的RIT RIT策略中使用Prostate策略。多价DOTA将用作辐射载体。 已合成了与前列腺癌有选择性结合的二价SCFV。 In the third project, the inventor of the "one bead, one peptide" combinatorial libraries has generated serine protease (Activase(R), TNKase(R) biodegradable linkers, stable in plasma, to reduce radiation doses to all normal tissues by eliminating radioisotope carriers from the blood "on demand". In the past, we showed that cathepsin-degradable peptides in放射线标记的mAB降低了肝辐射剂量。拟议的策略可降低所有正常组织的辐射剂量，并适用于其他放射性分析的靶向系统，无论是在发育中还是被批准的剂量。