Comparative Molecular Characterization and Pharmacokinetics of IgG1-Fc and Engineered Fc Human Antibody Variants to Insulin-like Growth Factor 2 Receptor (IGF2R)
Novel therapeutic approaches are much needed for the treatment of osteosarcoma. Targeted radionuclide therapy (TRT) and radioimmunotherapy (RIT) are promising approaches that deliver therapeutic radiation precisely to the tumor site. We have previously developed a fully human antibody, named IF3, th...
| Κύριοι συγγραφείς: | , , , , , , , , |
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| Μορφή: | Άρθρο |
| Γλώσσα: | English |
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MDPI AG
2023-08-01
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| Σειρά: | Molecules |
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| Διαθέσιμο Online: | https://www.mdpi.com/1420-3049/28/15/5839 |
| _version_ | 1827730990845394944 |
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| author | Chandra B. Prabaharan Sabeena Giri Kevin J. H. Allen Katrina E. M. Bato Therese R. Mercado Mackenzie E. Malo Jorge L. C. Carvalho Ekaterina Dadachova Maruti Uppalapati |
| author_facet | Chandra B. Prabaharan Sabeena Giri Kevin J. H. Allen Katrina E. M. Bato Therese R. Mercado Mackenzie E. Malo Jorge L. C. Carvalho Ekaterina Dadachova Maruti Uppalapati |
| author_sort | Chandra B. Prabaharan |
| collection | DOAJ |
| description | Novel therapeutic approaches are much needed for the treatment of osteosarcoma. Targeted radionuclide therapy (TRT) and radioimmunotherapy (RIT) are promising approaches that deliver therapeutic radiation precisely to the tumor site. We have previously developed a fully human antibody, named IF3, that binds to insulin-like growth factor 2 receptor (IGF2R). IF3 was used in TRT to effectively inhibit tumor growth in osteosarcoma preclinical models. However, IF3’s relatively short half-life in mice raised the need for improvement. We generated an Fc-engineered version of IF3, termed IF3δ, with amino acid substitutions known to enhance antibody half-life in human serum. In this study, we confirmed the specific binding of IF3δ to IGF2R with nanomolar affinity, similar to wild-type IF3. Additionally, IF3δ demonstrated binding to human and mouse neonatal Fc receptors (FcRn), indicating the potential for FcRn-mediated endocytosis and recycling. Biodistribution studies in mice showed a higher accumulation of IF3δ in the spleen and bone than wild-type IF3, likely attributed to abnormal spleen expression of IGF2R in mice. Therefore, the pharmacokinetics data from mouse xenograft models may not precisely reflect their behavior in canine and human patients. However, the findings suggest both IF3 and IF3δ as promising options for the RIT of osteosarcoma. |
| first_indexed | 2024-03-11T00:20:24Z |
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| id | doaj.art-48fe470b2a6848f39dc41d8d274e15e4 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T00:20:24Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-48fe470b2a6848f39dc41d8d274e15e42023-11-18T23:19:33ZengMDPI AGMolecules1420-30492023-08-012815583910.3390/molecules28155839Comparative Molecular Characterization and Pharmacokinetics of IgG1-Fc and Engineered Fc Human Antibody Variants to Insulin-like Growth Factor 2 Receptor (IGF2R)Chandra B. Prabaharan0Sabeena Giri1Kevin J. H. Allen2Katrina E. M. Bato3Therese R. Mercado4Mackenzie E. Malo5Jorge L. C. Carvalho6Ekaterina Dadachova7Maruti Uppalapati8Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, CanadaCollege of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5E5, CanadaCollege of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5E5, CanadaDepartment of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, CanadaDepartment of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, CanadaCollege of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5E5, CanadaCollege of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5E5, CanadaCollege of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5E5, CanadaDepartment of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, CanadaNovel therapeutic approaches are much needed for the treatment of osteosarcoma. Targeted radionuclide therapy (TRT) and radioimmunotherapy (RIT) are promising approaches that deliver therapeutic radiation precisely to the tumor site. We have previously developed a fully human antibody, named IF3, that binds to insulin-like growth factor 2 receptor (IGF2R). IF3 was used in TRT to effectively inhibit tumor growth in osteosarcoma preclinical models. However, IF3’s relatively short half-life in mice raised the need for improvement. We generated an Fc-engineered version of IF3, termed IF3δ, with amino acid substitutions known to enhance antibody half-life in human serum. In this study, we confirmed the specific binding of IF3δ to IGF2R with nanomolar affinity, similar to wild-type IF3. Additionally, IF3δ demonstrated binding to human and mouse neonatal Fc receptors (FcRn), indicating the potential for FcRn-mediated endocytosis and recycling. Biodistribution studies in mice showed a higher accumulation of IF3δ in the spleen and bone than wild-type IF3, likely attributed to abnormal spleen expression of IGF2R in mice. Therefore, the pharmacokinetics data from mouse xenograft models may not precisely reflect their behavior in canine and human patients. However, the findings suggest both IF3 and IF3δ as promising options for the RIT of osteosarcoma.https://www.mdpi.com/1420-3049/28/15/5839osteosarcoma (OS)insulin-like growth factor 2 receptor (IGF2R)monoclonal antibodiesneonatal Fc receptor (FcRn)radioimmunotherapy (RIT) |
| spellingShingle | Chandra B. Prabaharan Sabeena Giri Kevin J. H. Allen Katrina E. M. Bato Therese R. Mercado Mackenzie E. Malo Jorge L. C. Carvalho Ekaterina Dadachova Maruti Uppalapati Comparative Molecular Characterization and Pharmacokinetics of IgG1-Fc and Engineered Fc Human Antibody Variants to Insulin-like Growth Factor 2 Receptor (IGF2R) Molecules osteosarcoma (OS) insulin-like growth factor 2 receptor (IGF2R) monoclonal antibodies neonatal Fc receptor (FcRn) radioimmunotherapy (RIT) |
| title | Comparative Molecular Characterization and Pharmacokinetics of IgG1-Fc and Engineered Fc Human Antibody Variants to Insulin-like Growth Factor 2 Receptor (IGF2R) |
| title_full | Comparative Molecular Characterization and Pharmacokinetics of IgG1-Fc and Engineered Fc Human Antibody Variants to Insulin-like Growth Factor 2 Receptor (IGF2R) |
| title_fullStr | Comparative Molecular Characterization and Pharmacokinetics of IgG1-Fc and Engineered Fc Human Antibody Variants to Insulin-like Growth Factor 2 Receptor (IGF2R) |
| title_full_unstemmed | Comparative Molecular Characterization and Pharmacokinetics of IgG1-Fc and Engineered Fc Human Antibody Variants to Insulin-like Growth Factor 2 Receptor (IGF2R) |
| title_short | Comparative Molecular Characterization and Pharmacokinetics of IgG1-Fc and Engineered Fc Human Antibody Variants to Insulin-like Growth Factor 2 Receptor (IGF2R) |
| title_sort | comparative molecular characterization and pharmacokinetics of igg1 fc and engineered fc human antibody variants to insulin like growth factor 2 receptor igf2r |
| topic | osteosarcoma (OS) insulin-like growth factor 2 receptor (IGF2R) monoclonal antibodies neonatal Fc receptor (FcRn) radioimmunotherapy (RIT) |
| url | https://www.mdpi.com/1420-3049/28/15/5839 |
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