Development of a Bispecific Antibody Based Immunotherapy for Triple Negative Breast Cancer

开发基于双特异性抗体的三阴性乳腺癌免疫疗法

• 批准号: 9409569
• 负责人: Lloye M Dillon
• 金额: $ 22.5万
• 依托单位: DUALOGICS, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-13 至 2019-03-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9409569
• 关键词: Animal Model; Animals; Antibodies; Antibody Formation; Antibody Therapy; Antigen Targeting; Antigens; Binding; Biophysics; Bispecific Antibodies; Breast Cancer therapy; CD3 Antigens; Cancer Patient; Cancer cell line; Cancerous; Cell-Mediated Cytolysis; Cells; Clinical; Clinical Trials; Collaborations; Cytolysis; Development; Diagnostic tests; Dose; Drug Kinetics; Drug Targeting; ERBB2 gene; Engineering; Estrogen Receptors; Europe; Human; IgG1; Immune; Immune response; Immunoglobulin Fragments; Immunotherapy; In Vitro; Lead; Legal patent; Length; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mediating; Medical; Methods; Modernization; Molecular; Molecular Target; Molecular Weight; Monoclonal Antibodies; Mucin 1 protein; Mus; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Progesterone Receptors; Property; Solid; Specificity; Structure; T-Lymphocyte; TACSTD1 gene; Technology; Testing; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Treatment Efficacy; Tumor Antigens; Tumor Initiators; Variant; Xenograft Model; Xenograft procedure; antibody engineering; antigen binding; base; cGMP production; cancer cell; cancer therapy; clinical development; design; effective therapy; experimental study; immunogenicity; immunological synapse; improved; in vivo; malignant breast neoplasm; mouse model; mutant; neoplastic cell; novel; overexpression; phase 2 study; receptor; research clinical testing; scaffold; stable cell line; success; targeted treatment; thermostability; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth

Development of a Bispecific Antibody Based Immunotherapy for Triple Negative Breast Cancer. SUMMARY/ABSTRACT A promising and versatile approach to cancer treatment is the use of bispecific antibodies (bsAb) for immune cell redirection. In the two clinically approved therapies that pioneered this strategy, a bsAb drug acts as a molecular bridge between a T cell (via CD3 binding) and a tumor cell (via binding of a tumor associated antigen, or TAA). Simultaneous binding of both targets results in T cell mediated cytolysis of the tumor cell. The impressive success of this strategy has led to the development of similar bsAb immunotherapies for a wide variety of both hematological and solid cancers, resulting in over 15 drugs in active clinical trials. Triple negative breast cancer (TNBC) is an invasive breast cancer defined by a lack of the three distinct TAA required for available targeted breast cancer therapies. The lack of a robust TAA for TNBC has resulted in a dearth of modern targeted therapies and poor patient outcomes, and therefore development of novel TAA-targeted drugs for TNBC is a significant unmet medical need. OncoTAb Inc has developed a proprietary antibody (TAB 004) that recognizes a tumor specific variant of MUC1 (tMUC1). This antibody serves as the basis of OncoTAb’s Agkura Personal Score diagnostic test and has high specificity for a broad number of TNBC cell lines. In this proposal, we will develop and test a bsAb based immunotherapy for TNBC derived from the TAB 004 antibody. Historically, development of novel bsAb immunotherapies relies on the use of antibody fragments or complicated post-processing and purification, both of which can reduce stability, hinder manufacturability and prolong development. In order to alleviate these development hurdles, Dualogics, LLC has developed a proprietary bsAb platform, called OrthoMab, that retains the stability and manufacturability of native antibodies and is compatible with existing antibody sequences. Using the OrthoMab platform, we can rapidly generate a suite of bsAb molecules with varied size, binding valency, and geometric orientation; all of which have been shown to modulate the efficacy of bsAb immunotherapies. In Specific Aim 1 of this proposal we will generate and biophysically characterize three bsAb specific for tMUC1 and CD3, each with unique pharmacokinetic and functional properties (Ryan Hallett, Dualogics LLC). In Aim 2, we will measure specificity of each bsAb for TNBC cell lines and demonstrate targeted cytolysis of tumor cells by human PBMCs (Lloye Dillon, OncoTAb Inc.). In Aim 3, we will assess the pharmacokinetic properties of our top performing bsAb to determine dosing and evaluate efficacy in a TNBC xenograft mouse model (Ru Zhou, UNC-Charlotte). These experiments will validate T cell redirection by tMUC1 as a viable strategy for TNBC treatment and establish the basis of a phase II study to pursue further clinical development and pre-IND studies.

开发基于双特异性抗体的三阴性乳腺癌免疫治疗。 总结/摘要 癌症治疗的一种有前景的和通用的方法是使用双特异性抗体（bsAb）进行免疫调节。 单元重定向。在两种临床批准的疗法中，bsAb药物作为这一策略的先驱， T细胞（通过CD 3结合）和肿瘤细胞（通过结合肿瘤相关抗原）之间的分子桥 抗原或TAA）。两种靶标的同时结合导致T细胞介导的肿瘤细胞的细胞溶解。 这一策略令人印象深刻的成功导致了类似的bsAb免疫疗法的发展， 广泛的血液和实体癌症，导致超过15种药物在积极的临床试验中。三重 阴性乳腺癌（TNBC）是一种浸润性乳腺癌，其定义为缺乏所需的三种不同的TAA。 乳腺癌的靶向治疗。由于缺乏一个强有力的TNBC TAA， 现代靶向治疗和患者结局不佳，因此开发了新型TAA靶向药物 用于TNBC的药物是显著未满足的医疗需求。OncoTAb公司开发了一种专有抗体（TAB 004)识别肿瘤特异性MUC 1变体（tMUC 1）。这种抗体作为基础， OncoTAb的Agkura个人评分诊断测试，并对广泛数量的TNBC细胞具有高特异性。 线在这项提案中，我们将开发和测试一种基于bsAb的TNBC免疫疗法， 004抗体。历史上，新型bsAb免疫疗法的开发依赖于抗体的使用， 碎片或复杂的后处理和纯化，这两者都可以降低稳定性，阻碍 可制造性和可持续发展。为了缓解这些开发障碍，Dualogics，LLC 开发了一种专有的bsAb平台，称为OrthoMab，它保留了 天然抗体并与现有抗体序列相容。使用OrthoMab平台，我们可以 快速生成一套具有不同大小、结合价和几何取向的bsAb分子;所有这些 其已显示调节bsAb免疫疗法的功效。在本提案的具体目标1中， 我们将产生并生物物理表征三种对tMUC 1和CD 3特异性的bsAb，每种都具有独特的 药代动力学和功能特性（Ryan Hallett，Dualogics LLC）。在目标2中，我们将测量特异性 并且证明了人PBMC对肿瘤细胞的靶向细胞溶解（Lloye Dillon，OncoTAb Inc.）。在目标3中，我们将评估我们的最佳性能bsAb的药代动力学特性， 在TNBC异种移植小鼠模型中确定剂量并评价功效（Ru Zhou，UNC-Charlotte）。这些 实验将验证通过tMUC 1的T细胞重定向作为TNBC治疗的可行策略，并建立 II期研究的基础，以进行进一步的临床开发和IND前研究。