Targeting TGF-beta activation in tumors

靶向肿瘤中的TGF-β活化 摘要 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（TCR 4）和抑制溶细胞性CD 8 + T细胞和辅助性Th 1细胞。TGF-b是无处不在的 在哺乳动物中表达为同种型TGF-β 1、TGF-β 2和TGF-β 3，但通过非共价结合维持在无活性形式 与其前肽的相互作用，TGF-β的潜伏相关结构域（TGF-b）。整联蛋白avb 8结合到 TGF-β 1和TGF-β 3的表达，并介导其活化。生殖系或条件性遗传缺失研究 揭示了整合素avb 8介导的TGF-β活化对于TGF-β的体内活化是必需的，因此 avb 8作为TGF-β功能的关键调节剂。一般来说，整联蛋白是粘附分子并介导细胞粘附。 细胞与细胞外基质蛋白的附着。整联蛋白avb 8识别Arg-Gly-Asp（RGD）基序， 与纤连蛋白、玻连蛋白和潜在的TGF-β亚型相互作用，尽管它与纤连蛋白、玻连蛋白和潜在的TGF-β亚型的结合要强得多。 与其他含RGD的蛋白质相比，潜在的TGF-β（Ozawa，2016）。尽管TGF-b与肿瘤的发生有明显的关联， 尽管TGF-b和TGF-b信号通路与T细胞功能密切相关，但很少有靶向TGF-b的治疗是成功的，这主要是由于泛抑制剂 毒性为了解决这一治疗挑战，我们已经鉴定了一种小鼠单克隆抗体（AMHA-11）， 选择性阻断人整联蛋白AVB 8与其配体潜伏转化生长因子-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avb 8介导的TGF-b激活 同种型1和3，并且不抑制缺乏整合素结合RGD基序的TGF-β 2。此外，因为 由于其它α ν整联蛋白的冗余活性，细胞粘附不受AMHA-11干扰。这提供了更高的 仅干扰整联蛋白avb 8介导的TGF-β活化而不干扰残余的TGF-β活化的选择性程度 细胞粘附特性，这可能是不希望抑制的。此外，TGF-β的整体失活可能 具有不希望的副作用，因为TGF-β是必需的稳态上皮和免疫效应物。同相 1我们将鉴定抑制avb 8介导的TGF-β活化的高亲和力humAb，然后将它们按 它们在体外抑制TGF-β活化和调节T细胞活性的能力。我们还将在一个 小动物模型作为单一疗法和与抗PD-1组合。我们相信一种新的疗法 将导致这种更具选择性的方法。

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.