Targeting TGF-beta activation in tumors

靶向肿瘤中 TGF-β 的激活

• 批准号: 9907773
• 负责人: JAMES W LARRICK
• 金额: $ 22.5万
• 依托单位: LARIX BIOSCIENCE, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2021-09-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907773
• 关键词: Address; Affinity; Animal Model; Animals; Anti-inflammatory; Antibodies; Binding; CD8-Positive T-Lymphocytes; Cancer Patient; Cardiotoxicity; Cell Adhesion; Cell Adhesion Molecules; Cell physiology; Cell-Matrix Junction; Complex; Cytotoxic T-Lymphocytes; Data; Dose-Limiting; Down-Regulation; Drug Kinetics; Effectiveness; Epithelial; Exclusion; Extracellular Matrix Proteins; Fibronectins; Genetic; Human; Immune; Immune System Diseases; Immune Targeting; Immune response; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Vitro; Inflammatory Response; Integrin Binding; Integrins; Ligands; Malignant Neoplasms; Mammals; Mediating; Monoclonal Antibodies; Mus; Natural Immunity; Natural Killer Cells; Phase; Property; Protein Isoforms; Proteins; RGD (sequence); Regulatory T-Lymphocyte; Residual state; Safety; Signal Transduction; T cell response; T-Lymphocyte; Th1 Cells; Therapeutic; Time; Toxic effect; Transforming Growth Factor Beta 2; Transforming Growth Factor beta; Transforming Growth Factors; Transitional Cell Carcinoma; Tumor-infiltrating immune cells; Vitronectin; Work; anti-PD-1; assay development; human monoclonal antibodies; humanized mouse; immune checkpoint; in vitro Assay; in vivo; inhibitor/antagonist; integrin alphavbeta8; mouse model; neoplastic cell; novel anticancer drug; novel therapeutics; pre-clinical; side effect; targeted treatment; tumor; tumor microenvironment

Targeting TGF-b activation in tumors Abstract Transforming growth factor-β (TGF-β) drives immune dysfunction in the tumor microenvironment by inducing regulatory T cells (Tregs) and inhibiting cytolytic CD8+ T cells and helper Th1 cells. TGF-b is ubiquitously expressed in mammals as isoforms TGF-b1, -b2, and -b3, but is maintained in an inactive form by non-covalent interaction with its propeptide, the latency associated domain of TGF-b (LAP). The integrin avb8 binds to the LAP of TGF-b1 and TGF-b3 and mediates their activation. Germline or conditional genetic deletion studies have revealed that integrin avb8-mediated activation of TGF-b is essential for the in vivo activation of TGF-b, and thus avb8 acts as a key modulator of TGF-b function. In general, integrins are adhesion molecules and mediate the attachment of cells to extracellular matrix proteins. Integrin avb8 recognizes an Arg-Gly-Asp (RGD) motif and interacts with fibronectin, vitronectin, and latent TGF-β isoforms, although it binds considerably more strongly to latent TGF-β than to other RGD-containing proteins (Ozawa, 2016). Despite the clear association of TGF-b signaling and T cell function, few therapies that target TGF-b have been successful, largely due to pan-inhibitor toxicity. To address this therapeutic challenge, we have identified a mouse monoclonal antibody (AMHA-11) that selectively blocks the interaction of the human integrin avb8 with its ligand, latent transforming growth factor-b (TGF-b). The AMHA-11 antibody is unique in that it selectively perturbs the avb8-mediated activation of TGF-b isoforms 1 and 3 and does not inhibit TGF-b2, which lacks an integrin-binding RGD motif. Additionally, because of redundant activities of other av integrins, cell adhesion is not perturbed by AMHA-11. This affords a higher degree of selectivity in perturbing only integrin avb8-mediated activation of TGF-b activation and not the residual cell adhesion properties, which may be undesirable to inhibit. In addition, global inactivation of TGF-b is likely to have undesirable side effects since TGF-b is an essential homeostatic epithelial and immune effector. In Phase 1 we will identify high-affinity humAbs that inhibit avb8-mediated activation of TGF-b, then rank-order them in vitro for their ability to inhibit TGF-b activation and to modulate T cell activity. We will also evaluate them in a small animal model as monotherapy and in combination with anti-PD-1. We are confident that a novel therapy will result from this more selective approach.

靶向肿瘤中 TGF-b 的激活 抽象的 转化生长因子-β (TGF-β) 通过诱导肿瘤微环境中的免疫功能障碍 调节性 T 细胞 (Treg) 并抑制溶细胞 CD8+ T 细胞和辅助 Th1 细胞。 TGF-b 无处不在 在哺乳动物中以同种型 TGF-b1、-b2 和 -b3 表达，但通过非共价键维持非活性形式 与其前肽、TGF-b (LAP) 的潜伏相关域相互作用。整合素 avb8 结合 TGF-b1 和 TGF-b3 的 LAP 并介导它们的激活。种系或条件性基因缺失研究 揭示整合素 avb8 介导的 TGF-b 激活对于 TGF-b 的体内激活至关重要，因此 avb8 是 TGF-b 功能的关键调节剂。一般来说，整合素是粘附分子并介导 细胞与细胞外基质蛋白的附着。整合素 avb8 识别 Arg-Gly-Asp (RGD) 基序并 与纤连蛋白、玻连蛋白和潜在 TGF-β 亚型相互作用，尽管它与 潜在的 TGF-β 比其他含有 RGD 的蛋白质更显着（Ozawa，2016）。尽管 TGF-b 有明显关联 信号传导和 T 细胞功能，很少有针对 TGF-b 的治疗取得成功，这主要归功于泛抑制剂 毒性。为了应对这一治疗挑战，我们鉴定了一种小鼠单克隆抗体 (AMHA-11)， 选择性阻断人类整合素 avb8 与其配体、潜在转化生长因子-b 的相互作用 (TGF-b)。 AMHA-11 抗体的独特之处在于它选择性地干扰 avb8 介导的 TGF-b 激活 同工型 1 和 3，并且不抑制 TGF-b2，因为 TGF-b2 缺乏整合素结合 RGD 基序。另外，因为 由于其他 av 整合素的冗余活性，细胞粘附不受 AMHA-11 的干扰。这提供了更高的 仅干扰整合素 avb8 介导的 TGF-b 激活而不干扰残留的选择性程度 细胞粘附特性，这可能是不希望被抑制的。此外，TGF-b 的整体失活可能会 由于 TGF-b 是一种重要的稳态上皮和免疫效应物，因此具有不良副作用。同相 1 我们将鉴定抑制 avb8 介导的 TGF-b 激活的高亲和力 humAb，然后对它们进行排序 体外试验证明其具有抑制 TGF-b 激活和调节 T 细胞活性的能力。我们还将对它们进行评估 小动物模型作为单一疗法以及与抗 PD-1 联合疗法。我们相信新疗法 这将是这种更具选择性的方法的结果。