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 目前针对由细胞内癌蛋白驱动的肿瘤的方法。许多癌基因编码激活的 细胞内蛋白质的变体。虽然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，因此对细胞内靶无效。细胞内蛋白质的片段是 这些细胞由细胞表面的MHC分子呈递，但识别健康人和正常人之间的差异是具有挑战性的。 蛋白质和它们的致癌对应物通常是微小的。已经开发了许多共价抑制剂 针对细胞内癌蛋白，但大多数，像其他靶向治疗，引起耐药性， 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 是治愈性的，但大多数细胞内癌基因驱动的肿瘤未能响应这些药物。 我们提出了一个潜在的变革性创新，使用共价抑制剂联合靶向治疗 使用生物制剂进行免疫治疗。我们将开发“HapImmune”抗体， 与抑制剂共价连接并由MHC I类呈递于细胞表面的癌蛋白片段 癌细胞结合的抑制剂作为半抗原增加癌蛋白的免疫原性 片段药物和抗体的共同给药将通过参与免疫反应来启动癌细胞的杀伤。 攻击、抗原扩散和最终持久的抗肿瘤免疫。 令人信服的初步数据表明，HapImmune抗体可以产生针对几种 药物-肽缀合物。我们的多学科团队在癌症生物学、药物治疗和癌症治疗领域拥有互补的专业知识。 发现，抗体工程是很好的定位，以进一步发展和探索的适用性， HapImmune概念用于改善靶向治疗。我们将实现以下两个目标：（1）我们将 开发结合共价药物AMG 510的抗体，AMG 510与KRASG 12 C肽结合， MHC。尽管AMG 510有望彻底改变由KRASG 12 C驱动的癌症治疗，但其疗效 是短暂的我们将研究这种抗体在体外和体内选择性杀死癌症的功效 已经用AMG 510预处理的细胞。这些实验将批判性地评估 HapImmune方法使用癌症药物发现中的主要当前靶标。(2)我们将评估更广泛的 HapImmune方法的适用性，使用不同的靶点-药物对，使用EGFR的共价抑制剂 和BTK。我们将开发针对这些结合物的抗体，这些结合物存在于适当的MHC分子上， 它们在基于细胞的测定中的功效。这些实验应该提供一个严格的测试， HapImmune方法的适用性和我们开发HapImmune抗体的能力。 如果成功，该项目将建立一个简单的管道，以产生潜在的变革性疗法 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.