Development of TGF-beta antagonists for cancer therapy

尽管tgf - β在癌变过程中作为肿瘤抑制因子和肿瘤启动因子具有双重作用，但我们实验室和其他实验室的临床前数据先前表明，拮抗tgf - β的策略可能会选择性地减少这种生长因子的不良肿瘤促进作用，同时保留对肿瘤抑制和正常体内平衡的理想作用。基于这些有希望的临床前结果，一种抗tgf - β抗体正处于治疗晚期癌症的早期临床试验阶段。然而，鉴于tgf - β的复杂生物学特性，用于癌症治疗的tgf - β拮抗剂的成功开发将取决于对这些药物如何起作用的清晰理解，以及如何选择将从这种治疗中受益的患者的相关问题。在2008财年，我们在了解抗tgf - β抗体在抑制肿瘤进展和转移中的作用机制方面取得了实质性进展。为此，我们利用转移性乳腺癌的4T1同基因小鼠移植模型，结合全局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，进行了深入的机制分析。我们发现，一种单克隆抗体（1D11， Genzyme公司）可以中和所有三种tgf - β亚型，通过对多个细胞区室的许多小分子效应的协同作用，抑制肿瘤的发生和转移。靶细胞包括肿瘤细胞本身、免疫监视系统的组成部分和微血管。该抗体的大部分总体功效是由于增强的抗肿瘤免疫监视，涉及免疫系统的先天和适应性臂。除了已知的tgf - β对细胞毒性t细胞功能的抑制作用外，我们还发现了一种新的机制，即肿瘤诱导的tgf - β进一步破坏免疫系统的CD8+臂，通过il -17依赖机制为肿瘤提供直接的营养支持。tgf -抗体逆转了这两种作用。我们认为，局部分布的抗tgf - β抗体作用于肿瘤部位或附近的多个细胞靶点的机制可能是该药物意外低毒性的关键。这些数据对于临床生物标志物的开发和理解这类tgf - β拮抗剂影响肿瘤而非正常组织的选择性的生物学基础具有重要意义。

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.