An antibody-tumor necrosis factor fusion protein that synergizes with oxaliplatin for treatment of colorectal cancer
| Autor: | Davor Bajic, Dario Neri, Kerry A. Chester |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Necrosis medicine.drug_class Colorectal cancer Recombinant Fusion Proteins Antineoplastic Agents Monoclonal antibody Mice 03 medical and health sciences 0302 clinical medicine Carcinoembryonic antigen Cell Line Tumor medicine Animals Humans 030304 developmental biology 0303 health sciences biology Tumor Necrosis Factor-alpha Chemistry Transfection medicine.disease Fusion protein 3. Good health Oxaliplatin 030104 developmental biology Oncology 030220 oncology & carcinogenesis Colonic Neoplasms Cancer research biology.protein Tumor necrosis factor alpha Fluorouracil medicine.symptom Antibody Single-Chain Antibodies medicine.drug |
| Popis: | We have cloned and characterized a novel fusion protein (Sm3E-TNF), consisting of the monoclonal antibody Sm3E in single-chain Fv fragment format, fused to murine tumor necrosis factor. The protein, which was expressed in mammalian cells and purified as a non-covalent stable homotrimer, bound to the cognate carcinoembryonic antigen (CEA) and retained tumor necrosis factor activity. A quantitative biodistribution experiment, performed in immunocompetent mice with CT26 colon carcinomas transfected with human CEA, revealed that Sm3E-TNF was able to preferentially accumulate in the tumors with excellent selectivity (tumor:blood ratio = 56:1, twenty-four hours after intravenous administration). The fusion protein mediated a rapid hemorrhagic necrosis of a large portion of the tumor mass, but a rim survived and eventually regrew. Surprisingly, the combination of Sm3E-TNF with 5-fluorouracil led to a reduction of therapeutic activity, while a combination with oxaliplatin led to a prolonged stabilization, with complete tumor eradication in 40% of treated mice. These therapy results were confirmed in a second immunocompetent mouse model of colorectal cancer (CEA-transfected C51 tumors) and provide a rationale for the possible clinical use of oxaliplatin in combination with fully-human antibody-TNF fusions. |
| Databáze: | OpenAIRE |
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