Novel biologics platform for targeting tumors driven by intracellular oncoproteins

用于靶向细胞内癌蛋白驱动的肿瘤的新型生物制剂平台

基本信息

批准号：
10533364
负责人：
SHOHEI KOIDE
金额：
$ 23.3万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10533364
关键词：
Address Alleles Antibodies Antineoplastic Agents Binding Biological Assay Biological Products Bite Cancer Biology Cell Therapy Cell surface Cells Clinic Complex Data Drug Targeting Effector Cell Elements Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epitope spreading Extracellular Protein Goals Haptens Immune Immune checkpoint inhibitor Immunoglobulin G Immunotherapy In Vitro Interdisciplinary Study Link MHC Class I Genes Malignant Neoplasms Natural Killer Cells Oncogenes Oncogenic Oncoproteins Peptide/MHC Complex Peptides Pharmaceutical Preparations Positioning Attribute Proteins Resistance Solid Neoplasm Surface Technology Testing Therapeutic Translating Tumor Immunity antibody conjugate antibody engineering cancer cell cancer therapy cell killing chimeric antigen receptor T cells combination cancer therapy covalent bond drug discovery effectiveness evaluation efficacy evaluation experimental study immunogenicity improved in vivo inhibitor inhibitor therapy innovation multidisciplinary mutant new technology novel peptide drug protein degradation recruit response small molecule inhibitor targeted treatment technology platform tumor

项目摘要

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.

该项目的目的是建立一种新的平台技术，以解决的基本限制当前针对由细胞内癌蛋白驱动的肿瘤的方法。许多肿瘤基因被激活尽管生物制剂正在彻底改变癌症疗法，但它们并不容易输入细胞，因此对细胞内靶标无效。细胞内蛋白的碎片是由MHC分子在细胞表面上提出，但识别健康之间的差异是一项挑战蛋白质及其致癌物通常是几分钟。已经开发了许多共价抑制剂反对细胞内癌蛋白，但其中大多数像其他靶向疗法一样，引起抗药性，无法实现癌症治疗。相比之下，“免疫疗法”（例如，免疫检查点抑制剂，CAR-T细胞）可以要治愈，但大多数细胞内癌基因驱动的肿瘤无法对这些药物反应。我们提出了一种潜在的变革性创新，该创新将使用共价抑制剂靶向治疗。使用生物制剂进行免疫疗法。我们将开发有选择地识别的“ Hapimmune”抗体共价连接到抑制剂的癌蛋白的片段，并由MHC I类表面呈现癌细胞。共轭抑制剂是增加癌蛋白免疫原性的触觉碎片。药物和抗体的共同给药将通过接合免疫来杀死癌细胞攻击，抗原扩散以及最终耐用的抗肿瘤免疫组织切。引人入胜的初步数据表明，可以为几种生成Hapimmune抗体药物肽结合物。我们的多学科团队具有癌症生物学，药物的完整专业知识发现和抗体工程非常适合进一步发展和探索用于改善靶向治疗的Hapimmune概念。我们将执行以下两个目标：（1）我们将开发结合共价药物的抗体，AMG510与在一个上呈现的krasg12c peelede结合尽管预计AMG510将彻底改变针对Krasg12c驱动的癌症的治疗，但其有效是短暂的。我们将研究此类抗体在体外和体内选择性杀死癌症中的效率已通过AMG510预处理的细胞。这些实验将对 Hapimmune方法在癌症药物发现中使用主要目前的靶标。（2）我们将评估更广泛的使用EGFR的共价抑制剂，使用不同的目标毒品对的Hapimmune方法的适用性和btk。我们将开发与适当的MHC分子呈现并测试的这些结合物的抗体它们在基于细胞的测定中的效率。这些实验应对一般进行严格的测试 Hapimmune方法的适用性以及我们开发Hapimmune抗体的能力。如果成功，该项目将建立一条轻松的管道，以产生潜在的变革性疗法可以迅速转化为诊所。