Development of TGF-beta antagonists for cancer therapy

尽管TGF-β具有肿瘤抑制剂和肿瘤促进剂的双重作用， 致癌作用，我们实验室和其他人的临床前数据先前表明， 拮抗TGF-β的策略可以选择性地减少不期望的肿瘤促进作用， 这种生长因子的作用，同时保留了对肿瘤抑制的期望作用， 正常的体内平衡基于这些有希望的临床前结果， 用于治疗晚期癌症的早期临床试验但鉴于 TGF-β的复杂生物学，成功开发TGF-β拮抗剂用于癌症 治疗将取决于清楚地了解这些药物是如何工作的，以及相关的问题 如何选择能从这种治疗中受益的病人在2008财年， 在理解抗TGF-β抗体在肿瘤中的作用机制方面取得了实质性进展， 抑制肿瘤进展和转移。为此，我们深入开展了 使用转移性乳腺癌的4 T1同基因小鼠移植模型的机制分析 癌症，结合整体和候选基因表达分析，分子 组织学、免疫表型和免疫耗竭方法。我们发现一个单克隆 中和所有三种TGF-β同种型的抗体（1D 11，Genzyme Corp）抑制 肿瘤的发生和转移是通过多种小分子效应的协同作用， 细胞间室靶细胞包括肿瘤细胞本身，免疫系统的组成部分， 监控系统和微血管系统抗体的大部分总体功效是 由于增强的抗肿瘤免疫监视，涉及先天和适应性武器的 免疫系统除了已知的TGF-β对细胞毒性T细胞的抑制作用外， 功能，我们还确定了一种新的机制，使肿瘤诱导的TGF-β进一步颠覆 免疫系统的CD 8+臂通过以下方式为肿瘤提供直接营养支持： IL-17依赖性机制。TGF-β抗体逆转这两种作用。我们建议 抗TGF-β抗体对多种细胞局部分布作用机制 在肿瘤部位处或附近的靶点可能对于药物的出乎意料的低毒性是关键的。 剂这些数据对临床生物标志物的开发和生物学特性的研究具有重要意义。 了解这类TGF-β拮抗剂选择性的生物学基础， 影响肿瘤而不是正常组织。

Despite the dual role for TGF-beta as both tumor suppressor and tumor promoter in carcinogenesis, preclinical data from our lab and others has previously suggested that strategies to antagonize TGF-beta may selectively reduce the undesirable tumor promoting effects of this growth factor, while sparing the desirable effects on tumor suppression and normal homeostasis. Based on these promising preclinical results, an anti-TGF-beta antibody is in early phase clinical trials for the treatment of advanced cancer. However, given the complex biology of TGF-beta, the successful development of TGF-beta antagonists for cancer therapy will depend on a clear understanding of how these agents work and the related question of how to select patients who will benefit from this type of treatment. In FY08, we have made substantial progress in understanding the mechanism of action of an anti-TGF-beta antibody in suppressing tumor progression and metastasis. To do this, we have performed in depth mechanistic analyses using the 4T1 syngeneic mouse transplantation model of metastatic breast cancer, in combination with global and candidate gene expression analysis, molecular histology, immunophenotyping and immunodepletion approaches. We have found that a monoclonal antibody (1D11, Genzyme Corp) that neutralizes all three TGF-beta isoforms suppresses tumorigenesis and metastasis through the synergism of many small molecular effects on multiple cellular compartments. Target cells include the tumor cell itself, components of the immune surveillance system, and the microvasculature. Most of the overall efficacy of the antibody is due to enhanced anti-tumor immune surveillance, involving both innate and adaptive arms of the immune system. In addition to the known suppressive effects of TGF-beta on cytotoxic T-cell function, we also identified a novel mechanism whereby tumor-induced TGF-beta further subverts the CD8+ arm of the immune system into providing direct trophic support for the tumor through an IL-17-dependent mechanism. TGF-beta antibodies reverse both these effects. We propose that the locally distributed mechanism of action of anti-TGF-beta antibodies on multiple cell targets at or near the tumor site may be critical for the unexpectedly low toxicity of the agent. These data have important implications for clinical biomarker development and for understanding the biological basis of the selectivity of this class of TGF-beta antagonist in affecting the tumor and not the normal tissues.