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Development of drug conjugates of R-spondin peptibodies for the treatment of colorectal cancer

开发用于治疗结直肠癌的 R-spondin 肽体药物缀合物

基本信息

批准号：
10696733
负责人：
Jie Cui
金额：
$ 40万
依托单位：
WNTRIX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10696733
关键词：
Affinity Amino Acids Antibodies Antibody-drug conjugates Antigen Targeting Automobile Driving Binding Binding Proteins Biological Assay Blood Chemical Analysis Cancer Etiology Cell Line Cells Cessation of life Chimeric Proteins Clinical Research Colon Carcinoma Colorectal Colorectal Cancer Cytotoxic agent DNA Damage Development Digit structure Dose Drug Delivery Systems Drug resistance Drug usage Duocarmycin Endocytosis Fc domain Funding GPR4 gene Gene Expression Gene Fusion Genetic Models Goals Growth Half-Life Heterogeneity Histopathology Human IgG1 Immune System Diseases Immune checkpoint inhibitor Immunoglobulin G Immunotherapeutic agent In Vitro LGR5 gene Leucine-Rich Repeat Ligands Link Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Mediating Microtubules Modality Monoclonal Antibodies Mus Mutate Neoplasm Metastasis Pathway interactions Patients Peptides Pharmaceutical Preparations Phase Play Pre-Clinical Model Property Protein Secretion Proteins Recurrence Relapse Role Series Signal Transduction Solubility Specificity System Testing Therapeutic Therapeutic Index Time Tissues Toxic effect Toxicology Tumor Promotion Up-Regulation WNT Signaling Pathway Work Xenograft Model Xenograft procedure analytical method antagonist anticancer treatment antitumor effect cancer cell cancer stem cell cell growth cell killing checkpoint therapy clinical development colon cancer cell line colon cancer patients colorectal cancer treatment cytotoxic dimer drug candidate drug development in vitro Model in vivo inhibitor mouse genetics mutant neoplastic cell novel novel strategies overexpression patient derived xenograft model patient subsets pharmacologic public health relevance pyrrolobenzodiazepine receptor targeted agent therapeutically effective tumor tumor eradication tumor growth tumor heterogeneity tumor initiation tumor xenograft ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY Colorectal cancer is still a major cause of cancer-related death in the world and only a small subset of patients benefits from therapy by immune checkpoint inhibitors. Antibody–drug conjugates (ADCs) are monoclonal antibodies (mAbs) that are covalently linked to cell-killing drugs and have emerged as a major modality in anti-cancer treatment. This approach combines high specificity of mAbs against their antigen targets with highly potent cytotoxic drugs, resulting in “armed” mAbs that deliver the payload (drug) to tumor cells with enriched levels of the antibody target. The approach has become a major modality of cancer therapeutics with several ADCs approved in the last few years. Leucine-rich repeat containing, G protein-coupled receptor 4, 5 and 6 (LGR4-6) are three related receptors that are highly upregulated in colorectal cancers. They bind R-spondins (RSPOs), a group of secreted proteins with high affinity and potentiate Wnt signaling. Aberrant RSPO-LGR signaling plays critical roles in tumor formation, progression, and drug resistance. In particular, LGR5 is enriched in cancer stem cells of colon cancer and LGR5-positive cells drive tumor growth and metastasis. However, LGR5-positive and -negative cells can interconvert and ADCs targeting LGR5 inhibited tumor growth but failed to completely eradicate tumors due to cancer cell plasticity. Remarkably, LGR5-negative cells still express LGR4 or LGR6 or both. We reasoned that simultaneous targeting LGR4-6 may overcome cancer cell plasticity and drug resistance. Recently, we demonstrated that a mutated form of RSPO can bind to LGR4-6 with high affinity without potentiating Wnt signaling. Drug conjugates of RSPO mutant fused to IgG1-Fc domain was able to inhibit tumor cell growth in vitro and in vivo. We have now generated a pyrrolobenzodiazepine dimer (PBD)-based drug conjugate of an RSPO2 mutant that showed potent anti-tumor effect in colon cancer models in vitro and in vivo. In this proposal we will evaluate the drug conjugate in a series of colon cancer models in vitro and in vivo and determine its tolerability in mice. These results and conclusions may, for the first time, validate PBD-conjugated RSPO-Fc protein as a novel approach for simultaneous targeting of LGR4-6 for colorectal cancer treatment and identify drug candidates for further development.

项目摘要结直肠癌仍然是世界上癌症相关死亡的主要原因，患者受益于免疫检查点抑制剂的治疗。抗体-药物缀合物（ADC）是单克隆抗体（mAb）是共价连接到细胞杀伤药物，并已成为一种抗癌治疗的主要方式。这种方法结合了mAb针对其用高效细胞毒性药物靶向抗原，产生“武装”单克隆抗体，在一些实施方案中，本发明提供了一种将抗体（药物）与具有富集水平的抗体靶标的肿瘤细胞结合的方法。该方法已成为一个主要的在过去的几年中批准了几种ADC的癌症治疗方式。富含亮氨酸重复 G蛋白偶联受体4、5和6（LGR 4 -6）是三种相关的受体，在结直肠癌中上调。它们结合R-spondins（RSPO），一组分泌蛋白，高亲和力和增强Wnt信号传导。异常RSPO-LGR信号转导在肿瘤中起关键作用形成、进展和耐药性。特别地，LGR 5富集于人肝癌的癌干细胞中。结肠癌和LGR 5阳性细胞驱动肿瘤生长和转移。然而，LGR 5阳性和 - 阴性细胞可以相互转化，靶向LGR 5的ADC抑制肿瘤生长，但不能抑制肿瘤生长。由于癌细胞的可塑性，可以彻底根除肿瘤。值得注意的是，LGR 5阴性细胞仍然表达LGR 4或LGR 6或两者。我们推断同时靶向LGR 4 -6可以克服癌细胞的可塑性和抗药性。最近，我们证明了RSPO的一种突变形式，可以以高亲和力结合LGR 4 -6而不增强Wnt信号传导。RSPO的药物缀合物与IgG 1-Fc结构域融合的突变体能够在体外和体内抑制肿瘤细胞生长。我们有现在产生了RSPO 2突变体的基于吡咯并苯并二氮杂卓二聚体（PBD）的药物缀合物，在体外和体内结肠癌模型中显示出有效的抗肿瘤作用。在本提案中，我们将在体外和体内的一系列结肠癌模型中评价药物缀合物，小鼠的耐受性。这些结果和结论可能首次验证了PBD共轭 RSPO-Fc蛋白作为同时靶向LGR 4 -6治疗结直肠癌的新方法治疗并确定候选药物以供进一步开发。