Novel biologics platform for targeting tumors driven by intracellular oncoproteins

该项目的目标是建立一种新的平台技术，以解决 目前由细胞内癌蛋白驱动的抗肿瘤方法。许多癌基因编码被激活 细胞内蛋白质的不同版本。尽管生物制剂正在给癌症治疗带来革命性的变化，但它们并不容易做到。 进入细胞，因此对细胞内靶标无效。细胞内蛋白质的片段是 由细胞表面的MHC分子呈现，但要认识到健康的 蛋白质及其致癌对应物通常是微小的。已开发出许多共价抑制剂 抗细胞内癌蛋白，但它们中的大多数，像其他靶向治疗一样，引起耐药性并未能 实现癌症治愈。相比之下，“免疫疗法”(例如，免疫检查点抑制剂、CAR-T细胞)可以 是治愈的，但大多数细胞内癌基因驱动的肿瘤对这些药物没有反应。 我们提出了一种潜在的变革性创新，它结合了使用共价抑制剂的靶向治疗。 使用生物制剂进行免疫治疗。我们将开发选择性识别的“HapImmune”抗体 与抑制物共价连接的癌蛋白片段，由MHC第I类呈现在表面 癌细胞。结合的抑制物起到半抗原的作用，可以增加癌蛋白的免疫原性。 碎片。药物和抗体的联合给药将通过激活免疫来启动对癌细胞的杀伤 攻击、抗原传播和最终持久的抗肿瘤免疫。 令人信服的初步数据表明，可以产生针对几种 药物-多肽结合物。我们的多学科团队在癌症生物学、药物方面具有互补的专业知识 发现，抗体工程处于有利地位，进一步开发和探索 改善靶向治疗的HapImmune概念。我们将实现以下两个目标：(1)我们将 开发与共价药物AMG510结合的抗体，AMG510与KRASG12C肽结合在一起 MHC。尽管AMG510有望为KRASG12C驱动的癌症治疗带来革命性的变化，但它的疗效 是短暂的。我们将检测这些抗体在体外和体内选择性杀伤肿瘤的效果。 经AMG510处理的细胞。这些实验将批判地评估 Hap免疫法是目前癌症药物发现中的一个主要靶点。(2)我们将评估更广泛的 使用不同靶向药物对、使用EGFR共价抑制剂的HapImmune方法的适用性 和BTK。我们将开发针对这些呈现在适当MHC分子上的结合物的抗体，并进行测试 它们在基于细胞的检测中的有效性。这些实验应该是对一般情况的严格测试 肝免疫方法的适用性和我们开发肝免疫抗体的能力。 如果成功，该项目将建立一条生产潜在变革性疗法的便捷管道。 这可以迅速转化为临床。

The goal of this project is to establish a new platform technology that addresses fundamental limitations of current approaches against tumors driven by intracellular oncoproteins. Many oncogenes encode activated versions of intracellular proteins. Although biologics are revolutionizing cancer therapy, they do not readily enter cells and thus are ineffective against intracellular targets. Fragments of intracellular proteins are presented by MHC molecules on cell surface, but it is challenging to recognize differences between healthy proteins and their oncogenic counterparts that are often minute. Many covalent inhibitors have been developed against intracellular oncoproteins, but most of them, like other targeted therapies, evoke resistance and fail to achieve cancer cures. By contrast, “immune therapies” (e.g., immune checkpoint inhibitors, CAR-T cells) can be curative, but most intracellular oncogene-driven tumors fail to respond to these agents. We propose a potentially transformative innovation that unites targeted therapy using covalent inhibitors with immune therapy using biologics. We will develop “HapImmune” antibodies that selectively recognize fragments of an oncoprotein covalently linked to an inhibitor and presented by MHC Class I on the surface of cancer cells. The conjugated inhibitor serves as a hapten that increases the immunogenicity of the oncoprotein fragments. Co-administration of drug and antibody will initiate killing of cancer cells by engaging immune attack, antigen spreading and ultimately durable anti-tumor immunity. Compelling preliminary data demonstrate that HapImmune antibodies can be generated against several drug-peptide conjugates. Our multi-disciplinary team with complementary expertise in cancer biology, drug discovery, and antibody engineering is well positioned to further develop and explore the applicability of the HapImmune concept for improving targeted therapy. We will execute the following two Aims: (1) We will develop antibodies that bind a covalent drug, AMG510 conjugated with a KRASG12C peptide presented on an MHC. Although AMG510 is expected to revolutionize therapy against cancers driven by KRASG12C, its efficacy is short-lived. We will examine the efficacy of such antibodies in selective killing in vitro and in vivo of cancer cells that have been pretreated with AMG510. These experiments will critically evaluate the impact of the HapImmune approach using a major current target in cancer drug discovery. (2) We will assess the broader applicability of the HapImmune approach using distinct target-drug pairs, using covalent inhibitors of EGFR and BTK. We will develop antibodies to these conjugates presented on appropriate MHC molecules and test their efficacy in cell-based assays. These experiments should provide a rigorous test of the general applicability of the HapImmune approach and our ability to develop HapImmune antibodies. If successful, this project will establish a facile pipeline to produce potentially transformative therapeutics that can be rapidly translated into clinic.