Dataset Information

A Study of JK08, an IL-15 Antibody Fusion Protein Targeting CTLA-4, in Patients With Unresectable Locally Advanced or Metastatic Cancer

ABSTRACT: This is a Phase 1/2, open-label, multi-center, first-in-human, dose escalation and cohort expansion study evaluating multiple doses and schedules of subcutaneously administered JK08 in patients with unresectable locally, advanced or metastatic cancer.

DISEASE(S): Cáncer Localmente Avanzado O Metastásico No Resecable,Pancreatic Adenocarcinoma,Skin Carcinoma,Small Cell Lung Cancer,Colorectal Cancer,Triple Negative Breast Cancer,Oesophageal Adenocarcinoma,Neoplasms,Ovarian Cancer,Tumor, Solid,Neoplasm Metastasis,Neoplasms, Second Primary,Clear Cell Papillary Renal Cell Carcinoma,Advanced Solid Tumor,Hepatocellular Carcinoma,Urothelial Cancer Of Renal Pelvis,Oesophageal Squamous Cell Carcinoma,Cervical Cancer,Endometrial Adenocarcinoma,Melanoma,Luminal Breast Cancer,Breast Cancer,Thyroid Cancer,Non-small Cell Lung Cancer,Head And Neck Cancer,Unresectable Locally Advanced Or Metastatic Cancer,Metastatic Cancer,Cancer

PROVIDER: 180 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Dendrimer clearing agents represent a unique class of compounds for use in multistep targeting (MST) in radioimmunotherapy and imaging. These compounds were developed to facilitate the removal of excess tumor-targeting monoclonal antibody (mAb) prior to administration of the radionuclide to minimize exposure of normal tissue to radiation. Clearing agents are designed to capture the circulating mAb, and target it to the liver for metabolism. Glycodendrons are ideally suited for MST applications as these highly branched compounds are chemically well-defined, thus advantageous over heterogeneous macromolecules. Previous studies have described glycodendron 3 as a clearing agent for use in three-step MST protocols, and early in vivo assessment of 3 showed promise. However, synthetic challenges have hampered its availability for further development. In this report we describe a new sequence of chemical steps which enables the straightforward synthesis and analytical characterization of this class of dendrons. With accessibility and analytical identification solved, we sought to evaluate both lower and higher generation dendrons for hepatocyte targeting as well as clearance of a model protein. We prepared a series of clearing agents where a single biotin is connected to glycodendrons displaying four, eight, sixteen or thirty-two ?-thio-N-acetylgalactosamine (?-SGalNAc) units, resulting in compounds with molecular weights ranging from 2 to 17 kDa, respectively. These compounds were fully characterized by LCMS and NMR. We then evaluated the capacity of these agents to clear a model (131)I-labeled single chain variable fragment antibody-streptavidin ((131)I-scFv-SAv) fusion protein from blood and tissue in mice, and compared their clearing efficiencies to that of a 500 kDa dextran-biotin conjugate. Glycodendrons and dextran-biotin exhibited enhanced blood clearance of the scFv-SAv construct. Biodistribution analysis showed liver targeting/uptake of the scFv-SAv construct to be 2-fold higher for compounds 1 to 4, as well as for the 500 kDa dextran, over saline. Additionally, the data suggest the glycodendrons clear through the liver, whereas the dextran through reticuloendothelial system (RES) metabolism.

Dataset Information

A Study of JK08, an IL-15 Antibody Fusion Protein Targeting CTLA-4, in Patients With Unresectable Locally Advanced or Metastatic Cancer

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