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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...

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Autores principales: Prabaharan, Chandra B., Giri, Sabeena, Allen, Kevin J. H., Bato, Katrina E. M., Mercado, Therese R., Malo, Mackenzie E., Carvalho, Jorge L. C., Dadachova, Ekaterina, Uppalapati, Maruti
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10420659/
https://www.ncbi.nlm.nih.gov/pubmed/37570809
http://dx.doi.org/10.3390/molecules28155839
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author Prabaharan, Chandra B.
Giri, Sabeena
Allen, Kevin J. H.
Bato, Katrina E. M.
Mercado, Therese R.
Malo, Mackenzie E.
Carvalho, Jorge L. C.
Dadachova, Ekaterina
Uppalapati, Maruti
author_facet Prabaharan, Chandra B.
Giri, Sabeena
Allen, Kevin J. H.
Bato, Katrina E. M.
Mercado, Therese R.
Malo, Mackenzie E.
Carvalho, Jorge L. C.
Dadachova, Ekaterina
Uppalapati, Maruti
author_sort Prabaharan, Chandra B.
collection PubMed
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.
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spelling pubmed-104206592023-08-12 Comparative Molecular Characterization and Pharmacokinetics of IgG1-Fc and Engineered Fc Human Antibody Variants to Insulin-like Growth Factor 2 Receptor (IGF2R) Prabaharan, Chandra B. Giri, Sabeena Allen, Kevin J. H. Bato, Katrina E. M. Mercado, Therese R. Malo, Mackenzie E. Carvalho, Jorge L. C. Dadachova, Ekaterina Uppalapati, Maruti Molecules Article 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. MDPI 2023-08-03 /pmc/articles/PMC10420659/ /pubmed/37570809 http://dx.doi.org/10.3390/molecules28155839 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Prabaharan, Chandra B.
Giri, Sabeena
Allen, Kevin J. H.
Bato, Katrina E. M.
Mercado, Therese R.
Malo, Mackenzie E.
Carvalho, Jorge L. C.
Dadachova, Ekaterina
Uppalapati, Maruti
Comparative Molecular Characterization and Pharmacokinetics of IgG1-Fc and Engineered Fc Human Antibody Variants to Insulin-like Growth Factor 2 Receptor (IGF2R)
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10420659/
https://www.ncbi.nlm.nih.gov/pubmed/37570809
http://dx.doi.org/10.3390/molecules28155839
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