Control of lethal prostate cancer with a bispecific av and a5b1 integrin antibody

摘要 全世界每年有30万人死于前列腺癌，其中大部分是由骨引起的。 转移，因为骨骼是大多数晚期乳腺癌患者临床疾病的唯一部位。 病我们对支撑高效和生命的机制的知识存在根本性的差距- 前列腺癌细胞威胁骨微环境的定植。我们的长期目标是 基于对骨病理生理学的分子理解，开发新的治疗策略 转移，以显着提高前列腺癌的生存和生活质量的结果。我们 实验室研究表明，前列腺癌细胞表达的两种不同但功能相关的整合素， 它们在骨微环境中的归巢、存活和致命扩散。这项研究的基本原理是， 同时靶向这2种整联蛋白的双特异性抗体将最佳地通过其自身的 交联作用机制，并提供有效的治疗策略。因此，一流的 靶向这些整联蛋白的双特异性抗体显示出与对照相比更优越的上级抗肿瘤活性 单独或组合的单特异性抗体。双特异性抗体的不同分子作用机制 抗体的定义。在用单特异性整联蛋白抗体中的一种或两种治疗后， 观察到整合素的上调，而相比之下，在双特异性免疫后整合素的下调。 通过诱导整合素的内化和溶酶体降解进行抗体治疗。我们的假设是 双特异性整合素抗体将阻止前列腺癌在骨中的危及生命的进展， 微环境我们计划通过三个具体目标来评估这一假设。首先，我们计划评估 双特异性抗体与单特异性抗体相比在骨的不同动物模型中的功效 复制临床疾病的关键方面的转移：骨髓的接种，与肿瘤的相互作用， 人骨源性基质细胞，加速生长并从骨中二次传播，最后， 成骨细胞表型的产生。第二，我们将进一步确定 通过评估其对上皮-间充质转化、失巢凋亡和凋亡的影响， 克隆存活率最后，我们将确定两种整合素表达的器官特异性， 比较这些整合素在前列腺癌和其他实体瘤骨转移中的表达， 在淋巴结和内脏器官中发现转移。我们的创新治疗策略， 前列腺癌在骨微环境中定植的分子机制是重要的， 它有可能显著延长前列腺癌患者的生存期并改善其生活质量。 乳腺癌等在骨中定植的实体瘤可能会利用相同的分子途径， 双特异性抗体策略在生物标志物支持的临床试验中的潜在意义和影响， 跟随.

ABSTRACT The majority of the 300,000 annual deaths worldwide from prostate cancer are strongly attributed to bone metastasis because the skeleton is the exclusive site of clinical disease in the majority of men with advanced illness. There is a fundamental gap in our knowledge of the mechanisms that underpin the efficient and life- threatening colonization of the bone microenvironment by prostate cancer cells. Our long-term goal is to develop novel therapeutic strategies based on a molecular understanding of the pathophysiology of bone metastases in order to significantly improve survival and quality of life outcomes in prostate cancer. Our laboratory studies implicate two different but functionally related integrins expressed by prostate cancer cells in their homing, survival and lethal spread within the bone microenvironment. The rationale of this study is that a bispecific antibody that simultaneously targets these 2 integrins would optimally neutralize their function via its cross-linking mechanism of action and deliver an efficacious therapeutic strategy. Accordingly, a first-in-class bispecific antibody targeting these integrins demonstrated superior antitumor activity compared to monospecific antibodies alone or in combination. A distinct molecular mechanism of action for the bispecific antibody was defined. Following treatment with either or both monospecific integrin antibodies, adaptive upregulation of the integrins was seen whereas by contrast, downregulation of integrins followed bispecific antibody treatment via induction of internalization and lysosomal degradation of integrins. Our hypothesis is that the bispecific integrin antibody will halt the life-threatening progression of prostate cancer in the bone microenvironment. We plan to evaluate this hypothesis with three specific aims. First, we plan to assess the efficacy of the bispecific antibody compared to monospecific antibodies in distinct animal models of bone metastases that replicate key dimensions of the clinical disease: seeding of the bone marrow, interaction with human bone-derived stromal cells, accelerated growth and secondary dissemination from bone, and finally, generation of an osteoblastic phenotype. Secondly, we will further define the mechanism of action of the bispecific integrin antibody by assessing its impact on epithelial-mesenchymal transition, anoikis and clonogenic survival. Finally, we will determine the organ-specificity of the expression of the two integrins by comparing the expression of these integrins in bone metastases from prostate cancer and other solid tumors to metastases found in lymph nodes and visceral organs. Our innovative therapeutic strategy to disable the molecular mechanisms of colonization of the bone microenvironment by prostate cancer is significant because it has the potential to significantly prolong survival and improve quality of life of patients with prostate cancer. Solid tumors that colonize bone such as breast cancer may leverage the same molecular pathways, expanding the potential significance and impact of the bispecific antibody strategy in biomarker-supported clinical trials to follow.