Pharmaceutical research · 2025
Enhanced Penetration and Retention of an Antibody in the Articular Cartilage Through Aggrecan Binding and Molecular Downsizing.
СтатьяНазвание и аннотация: Перевод в очереди
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Noguchi Yuki, Hoshino Maiko, Muraoka Masaru, Gupta Garvita, Sun Yang, Hironiwa Naoka, Tu Wenjie, Joyashiki Eri, Haraya Kenta, Kuramochi Taichi, Igawa Tomoyuki
Аннотация
PURPOSE: Delivering immunogloblin G (IgG) to the articular cartilage is a challenge and presents an obstacle in developing therapeutic antibodies for articular diseases. In this study, we focused on binding to the aggrecan-a key component of the cartilage matrix as a proteoglycan-and molecular downsizing to enhance the penetration and retention of antibodies in the articular cartilage.
METHODS: The control IgG (143 kDa), anti-aggrecan IgG (141 kDa), F(ab')2 (93.0 kDa), and Fab (44.9 kDa) were intra-articularly injected into a rabbit joint, and the concentrations of each molecule in synovial fluid, articular cartilage, and plasma were monitored.
RESULTS: Each molecule exhibited a similar elimination profile in synovial fluid. However, compared to the control IgG, anti-aggrecan IgG showed increased exposure in cartilage. Moreover, anti-aggrecan F(ab')2 exhibited even higher concentrations in cartilage, while the anti-aggrecan Fab demonstrated the highest and most long-lasting concentration profile in cartilage. Fluorescence imaging of the ex vivo cartilage penetration further supported the superior transport of the anti-aggrecan Fab and F(ab')2 compared to the control IgG and the anti-aggrecan IgG.
CONCLUSIONS: Our study demonstrates that binding to the cartilage matrix, in addition to molecular size, is important, and that their combination has a synergistic effect on the antibody exposure in the articular cartilage.
METHODS: The control IgG (143 kDa), anti-aggrecan IgG (141 kDa), F(ab')2 (93.0 kDa), and Fab (44.9 kDa) were intra-articularly injected into a rabbit joint, and the concentrations of each molecule in synovial fluid, articular cartilage, and plasma were monitored.
RESULTS: Each molecule exhibited a similar elimination profile in synovial fluid. However, compared to the control IgG, anti-aggrecan IgG showed increased exposure in cartilage. Moreover, anti-aggrecan F(ab')2 exhibited even higher concentrations in cartilage, while the anti-aggrecan Fab demonstrated the highest and most long-lasting concentration profile in cartilage. Fluorescence imaging of the ex vivo cartilage penetration further supported the superior transport of the anti-aggrecan Fab and F(ab')2 compared to the control IgG and the anti-aggrecan IgG.
CONCLUSIONS: Our study demonstrates that binding to the cartilage matrix, in addition to molecular size, is important, and that their combination has a synergistic effect on the antibody exposure in the articular cartilage.