Increasing the efficacy of MTI-101 in MM using Ab conjugation strategies

使用抗体缀合策略提高 MTI-101 在 MM 中的功效

• 批准号: 8591600
• 负责人: Lori Hazlehurst
• 金额: $ 28.83万
• 依托单位: MODULATION THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-31 至 2014-01-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8591600
• 关键词: Antibodies; Binding; Bone Marrow; CD44 gene; Caspase; Cell Death; Cells; Clinical; Complex; Cyclic Peptides; Cyclization; Development; Disease; Drug resistance; Generations; Goals; Grant; Half-Life; Home environment; Hour; In Vitro; Integrin alpha4beta1; Integrins; Laboratories; Lead; MSX1 gene; Malignant Neoplasms; Modeling; Multi-Drug Resistance; Multiple Myeloma; Necrosis; Neoplasm Metastasis; Newly Diagnosed; Outcome; Pathway interactions; Patients; Peptides; Phenotype; Plasma Cells; Recurrent disease; Relapse; Resistance; Solid Neoplasm; Specificity; Technology; Therapeutic; Therapeutic Index; Translations; base; bone; cell killing; chemotherapy; design; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; neoplastic cell; novel; novel strategies; novel therapeutics; promoter; public health relevance; response; small molecule; tumor

DESCRIPTION (provided by applicant): The majority of multiple myeloma (MM) patients will initially respond to standard chemotherapy. However, eventually relapse of the disease, associated with a multi-drug resistant phenotype, contributes to poor clinical outcomes. Modulation Therapeutics is dedicated towards developing strategies for targeting cancers like MM that home or metastasize to the bone. Our current lead compound binds a CD44/VLA-4 complex and induces necrotic cell death. The in vivo efficacy of MTI-101 has been demonstrated using two in vivo myeloma models which consider the bone marrow microenvironment when evaluating tumor response. Our lead compound is a cyclic peptide which reduces concerns of proteolytic degradation. However, the efficacy of the compound may still be limited by a short circulating half-life often typical of peptide based therapies. The oveall goal of this proposal is to utilize antibody conjugation strategies designed to increase the therapeutic window of our lead compound. The first goal of this proposal is to determine whether conjugation of MTI-101 to a non-targeting antibody will increase the in vivo efficacy of the compound. The second goal of this proposal is to generate and evaluate a conjugate of MTI-101 and a CD138-targeting antibody to determine if we can increase specificity of the compound and thereby increase the therapeutic window of our lead compound.

描述（由申请人提供）：大多数多发性骨髓瘤（MM）患者最初对标准化疗有反应。然而，与多药耐药表型相关的疾病的最终复发导致不良的临床结果。Modulation Therapeutics致力于开发针对MM等癌症的策略，这些癌症可能会转移到骨骼。我们目前的先导化合物结合CD 44/VLA-4复合物并诱导坏死细胞死亡。MTI-101的体内功效已使用两种体内骨髓瘤模型证明，所述模型在评价肿瘤反应时考虑骨髓微环境。我们的先导化合物是一种环状肽，可减少蛋白水解降解的担忧。然而，化合物的功效仍然可能受到基于肽的疗法通常具有的短循环半衰期的限制。该提议的首要目标是利用设计用于增加我们的先导化合物的治疗窗口的抗体缀合策略。该提议的第一个目标是确定MTI-101与非靶向抗体的缀合是否会增加化合物的体内功效。该提议的第二个目标是产生和评估MTI-101和靶向CD 138的抗体的缀合物，以确定我们是否可以增加化合物的特异性，从而增加我们的先导化合物的治疗窗口。