Antibody fragment drug conjugates for cancer therapy

用于癌症治疗的抗体片段药物缀合物

• 批准号: 6932141
• 负责人: PAUL J. CARTER
• 金额: $ 16.51万
• 依托单位: SEATTLE GENETICS, 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 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6932141
• 关键词: CHO cells; Hodgkin' s disease; SCID mouse; SDS polyacrylamide gel electrophoresis; antitumor antibody; biotechnology; capillary electrophoresis; cytotoxicity; disease /disorder model; drug design /synthesis /production; immunoconjugates; immunoglobulin G; immunoglobulin structure; monoclonal antibody; neoplasm /cancer immunotherapy; nonHodgkin' s lymphoma; nonhuman therapy evaluation; oligopeptides; pharmacokinetics; therapy design /development; xenotransplantation

DESCRIPTION (provided by applicant): Antibodies are the most rapidly expanding class of drugs to treat human disease, including cancer. However, current antibody therapies in oncology are seldom, if ever, curative. Thus there remains a need to improve the response rate and duration for anti-cancer antibodies. Conjugation to cytotoxic drugs is one of the most promising ways to enhance the antitumor efficacy of antibodies. Significant progress has been made in optimizing the chemistry of drug conjugates, whereas their antibody component remains to be optimized. E.g., the chimeric anti-CD30 antibody, cAC10, has been conjugated via plasma stable peptide linkers to the potent cytotoxic drug, monomethyl auristatin E (MMAE). This culminated in efficacy of cAC10 IgG-MMAE in SCID mouse xenograft models of anaplastic large cell lymphoma (ALCL) and Hodgkin's disease at doses well below the maximally tolerated dose. This application builds upon these earlier studies with cAC10 IgG-MMAE and includes key personnel (Drs. P. Senter and J. Francisco), instrumental to the prior work. A vexing challenge with antibody drug conjugates is toxicity due to release of drug at non-tumor sites. Unfortunately, drug liberation following conjugate catabolism appears to be the unavoidable ultimate in vivo fate of IgG drug conjugates. The use of antibody fragments for drug conjugation offers a potential way to circumvent the catabolic fate of IgG drug conjugates. This reflects that antibody fragments are eliminated rapidly and primarily by renal filtration. If antibody fragment conjugates are excreted with drug still attached, this will lessen the exposure of non-tumor sites to free drug and may reduce the observed toxicity. This proposal tests the feasibility of using antibody fragment drug conjugates for cancer therapy. Diabody, minibody and scFv-Fc antibody fragments of the anti-CD30 MAb, AC10, will be prepared and conjugated to MMAE. These antibody fragment drug conjugates plus control conjugates will be compared in their in vitro antitumor activities. Potent antibody conjugates will be compared in their biodistribution and efficacy in a SCID mouse xenograft model of ALCL as well as their pharmacokinetics and toxicity in SCID mice. Robust in vivo efficacy with any antibody fragment drug conjugate with acceptable toxicities would provide the foundation for a future SBIR Phase II application. Our ultimate goal is to use an optimized antibody fragment drug conjugate to treat CD30 positive hematologic malignancies such as Hodgkin's disease, ALCL and cutaneous T cell lymphoma. Advances made with anti-CD30 antibody fragment drug conjugates are anticipated to be broadly applicable to other antibodies with therapeutic potential.

描述（由申请人提供）：抗体是治疗人类疾病（包括癌症）发展最快的一类药物。然而，目前肿瘤学中的抗体疗法很少（如果有的话）能够治愈。因此，仍然需要提高抗癌抗体的响应率和持续时间。与细胞毒性药物结合是增强抗体抗肿瘤功效最有前途的方法之一。在优化药物缀合物的化学方面已经取得了重大进展，但其抗体成分仍有待优化。 例如，嵌合抗 CD30 抗体 cAC10 已通过血浆稳定肽接头与有效的细胞毒性药物单甲基 auristatin E (MMAE) 缀合。最终，cAC10 IgG-MMAE 在间变性大细胞淋巴瘤 (ALCL) 和霍奇金病的 SCID 小鼠异种移植模型中以远低于最大耐受剂量的剂量发挥功效。该应用程序建立在这些早期的 cAC10 IgG-MMAE 研究的基础上，包括对之前的工作有帮助的关键人员（P. Senter 博士和 J. Francisco）。 抗体药物缀合物的一个令人烦恼的挑战是由于药物在非肿瘤部位释放而产生的毒性。不幸的是，缀合物分解代谢后的药物释放似乎是 IgG 药物缀合物不可避免的最终体内命运。使用抗体片段进行药物偶联提供了一种避免 IgG 药物偶联物分解代谢命运的潜在方法。这反映出抗体片段被快速消除并且主要通过肾滤过消除。如果抗体片段缀合物在药物仍附着的情况下被排出，这将减少非肿瘤位点对游离药物的暴露，并可能减少观察到的毒性。 该提案测试了使用抗体片段药物缀合物进行癌症治疗的可行性。 将制备抗CD30 MAb、AC10的双抗体、微型抗体和scFv-Fc抗体片段，并将其与MMAE缀合。将比较这些抗体片段药物缀合物和对照缀合物的体外抗肿瘤活性。将比较有效的抗体缀合物在 ALCL 的 SCID 小鼠异种移植模型中的生物分布和功效，以及它们在 SCID 小鼠中的药代动力学和毒性。具有可接受毒性的任何抗体片段药物缀合物的强大体内功效将为未来 SBIR II 期应用奠定基础。我们的最终目标是使用优化的抗体片段药物偶联物来治疗 CD30 阳性血液恶性肿瘤，例如霍奇金病、ALCL 和皮肤 T 细胞淋巴瘤。抗 CD30 抗体片段药物缀合物取得的进展预计将广泛适用于具有治疗潜力的其他抗体。