Novel Protein Engineered Drug Conjugates Targeting Phosphatidylserine for the Treatment of Breast Cancer

靶向磷脂酰丝氨酸的新型蛋白质工程药物缀合物用于治疗乳腺癌

• 批准号: 10653821
• 负责人: Rolf A Brekken
• 金额: $ 46.63万
• 依托单位: BAYLOR UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-05 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653821
• 关键词: 4T1; Acceleration; Acute; Angiogenesis Inhibition; Antibodies; Antibody-drug conjugates; Antimitotic Agents; Antineoplastic Agents; Binding; Biological Assay; Biology; Blood Vessels; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Treatment; Breathing; Cathepsin L; Cathepsins B; Cell Death; Cell division; Cell membrane; Cells; Characteristics; Comparative Study; Cytotoxic agent; Diffuse; Drug Delivery Systems; Drug Design; Drug Kinetics; Endothelial Cells; Enzymes; Evaluation; Exposure to; Future; Glutaminase; Growth; Half-Life; Home; Human; Immune; Inbred BALB C Mice; Individual; Libraries; MDA MB 231; Malignant Neoplasms; Mammary Neoplasms; Mediating; Modality; Monoclonal Antibodies; Mouse Mammary Tumor Virus; Mus; Myeloid-derived suppressor cells; Necrosis; Normal Cell; Patients; Penetration; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Phosphatidylserines; Plasma; Plasmin; Prodrugs; Protein Engineering; Research; Rest; SCID Mice; Safety; Signal Transduction; Therapeutic Agents; Time; Toxic effect; Treatment Efficacy; Tumor Immunity; Tumor Markers; Tumor-Associated Vasculature; Tumor-associated macrophages; Urokinase; Validation; Vascular Endothelial Cell; Xenograft procedure; analog; anti-cancer; anti-cancer therapeutic; anti-tumor immune response; antibody conjugate; antiproliferative agents; beta 2-glycoprotein I; bioluminescence imaging; cancer cell; catalyst; chemical stability; chemical synthesis; clinically relevant; cytokine; cytotoxicity; design; drug development; drug discovery; extracellular; improved; in vitro Assay; in vivo; innovation; mouse model; nanomolar; neoplastic cell; next generation; novel; orthotopic breast cancer; polyoma middle tumor antigen; side effect; small molecule; targeted treatment; therapeutically effective; triple-negative invasive breast carcinoma; tubulin polymerization inhibitor; tumor; tumor growth; tumor microenvironment; tumor specificity; tumor-immune system interactions

7. Project Summary/Abstract There remains an urgent, and largely unmet need for the advancement of highly selective and effective therapeutic agents for the treatment of metastatic and triple negative breast cancer. This proposal advances an innovative and promising strategy focused on the first time synthesis and evaluation of betabody-drug conjugates (BDCs), which feature engineered proteins (referred to as betabodies) that target phosphatidylserine (PS). PS is selectively exposed on the outer leaflet of the plasma membrane of cancer cells and endothelial cells in the tumor microenvironment, but is confined to the inner leaflet of the plasma membrane of normal cells. This provides an exquisite opportunity for selective targeting of potent small-molecule anticancer payloads (KGP18 and KGP156) to the tumor microenvironment. Betabodies are smaller allowing for better tumor penetration compared with previously evaluated PS-selective antibodies, which demonstrated poor distribution beyond the vasculature. BDCs are designed to selectively release KGP18 and KGP156 extracellularly by enzymes (cathepsin B, urokinase-type plasminogen activator, and plasmin) that are upregulated and/or demonstrate enhanced activity by breast cancer cells and associated tumor vasculature. KGP18 and KGP156 are potent inhibitors of tubulin polymerization and demonstrate dual mechanism of action functioning as remarkably active antiproliferative agents (cytotoxicity in low nM to pM range) and as profoundly effective vascular disrupting agents, which impart irreversible damage to tumor-associated vasculature ultimately leading to tumor necrosis. These synthetic benzosuberene-based payloads (KGP18 and KGP156) will be evaluated in comparative studies to monomethyl-auristatin E (MMAE), which is a payload of choice in many clinically relevant antibody-drug conjugates. It should be noted that VDAs are mechanistically distinct from the well-studied angiogenesis inhibiting agents. Two individual delivery strategies will be investigated. KGP18 and KGP156 will be synthetically functionalized with distinct, protease-selective peptide-based linkers rendering the drug-linker prodrug constructs biologically inert until cleaved by specific proteases that are present at high levels in the tumor microenvironment, thus selectively releasing the potent payload (KGP18 or KGP156). In a second strategy, BDCs will be prepared from the best drug-protease selective linker constructs. The hypothesis is that appropriately designed drug-linker constructs and their corresponding BDCs tethered to these highly potent payloads (KGP18 or KGP156) will demonstrate high selectivity for tumor vasculature and tumor cells. Pharmacokinetic studies will evaluate the release of the effector drugs from their corresponding constructs and conjugates. The efficacy and selectivity of these drug-linker constructs and BDCs will be evaluated using cell-based studies and established murine orthotopic breast cancer models (MDA-MB-231 human xenografts and syngeneic 4T1 tumors). In summary, it is expected that each strategy will result in tumor-specific drug delivery and potent anti-tumor activity.

7. 项目总结/文摘

项目成果

Structure Guided Design, Synthesis, and Biological Evaluation of Oxetane-Containing Indole Analogues.

含氧杂环丁烷吲哚类似物的结构引导设计、合成和生物学评价。

• DOI: 10.1016/j.bmc.2023.117400
• 发表时间: 2023
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: Ren,Wen;Vairin,Rebecca;Ward,JacobD;Francis,Ricardo;VanNatta,Jenny;Bai,Ruoli;Tankoano,PouguiniseliE;Deng,Yuling;Hamel,Ernest;Trawick,MaryLynn;Pinney,KevinG
• 通讯作者: Pinney,KevinG