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，解决 目前针对细胞内癌蛋白驱动的肿瘤的方法。许多癌基因编码激活 细胞内蛋白质的版本。尽管生物制剂正在彻底改变癌症治疗，但它们并不容易 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，但识别健康人之间的差异具有挑战性 蛋白质及其致癌对应物通常很小。已开发出许多共价抑制剂 对抗细胞内癌蛋白，但其中大多数与其他靶向疗法一样，会引起耐药性并且无法发挥作用 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 具有治愈性，但大多数细胞内癌基因驱动的肿瘤无法对这些药物产生反应。 我们提出了一项潜在的变革性创新，将使用共价抑制剂的靶向治疗结合起来 使用生物制剂进行免疫治疗。我们将开发“HapImmune”抗体，选择性识别 与抑制剂共价连接并由 I 类 MHC 呈递在肿瘤表面的癌蛋白片段 癌细胞。缀合抑制剂充当半抗原，增加癌蛋白的免疫原性 碎片。药物和抗体的共同给药将通过免疫系统启动杀死癌细胞 攻击、抗原扩散以及最终持久的抗肿瘤免疫力。 令人信服的初步数据表明 HapImmune 抗体可以针对多种 药物-肽缀合物。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 发现和抗体工程处于有利地位，可以进一步开发和探索该技术的适用性 HapImmune 改善靶向治疗的概念。我们将实现以下两个目标：（1）我们将 开发结合共价药物的抗体，AMG510 与 KRASG12C 肽结合，呈现在 MHC。尽管 AMG510 有望彻底改变 KRASG12C 驱动的癌症治疗方法，但其功效 是短暂的。我们将检查此类抗体在体外和体内选择性杀死癌症的功效 已用 AMG510 预处理的细胞。这些实验将严格评估 HapImmune 方法使用当前癌症药物发现的主要目标。 (2) 我们将评估更广泛的 使用不同靶点药物对、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在适当的 MHC 分子上呈现的缀合物的抗体并进行测试 它们在基于细胞的测定中的功效。这些实验应该对一般性提供严格的测试 HapImmune 方法的适用性以及我们开发 HapImmune 抗体的能力。 如果成功，该项目将建立一个便捷的管道来生产潜在的变革性疗法 可以快速转化为临床。

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.