Influence of Fc modifications and IgG subclass on biodistribution of humanized antibodies targeting L1CAM Journal Article
| Authors: | Sharma, S. K.; Suzuki, M.; Xu, H.; Korsen, J. A.; Samuels, Z.; Guo, H.; Nemieboka, B.; Piersigilli, A.; Edwards, K. J.; Cheung, N. K. V.; Lewis, J. S. |
| Article Title: | Influence of Fc modifications and IgG subclass on biodistribution of humanized antibodies targeting L1CAM |
| Abstract: | Immuno-PET is a powerful tool to noninvasively characterize the in vivo biodistribution of engineered antibodies. Methods: L1 cell adhesion molecule–targeting humanized (HuE71) IgG1 and IgG4 antibodies bearing identical variable heavy- and light-chain sequences but different fragment crystallizable (Fc) portions were radiolabeled with 89Zr, and the in vivo biodistribution was studied in SKOV3 ovarian cancer xenografted nude mice. Results: In addition to showing uptake in L1 cell adhesion molecule–expressing SKOV3 tumors, as does its parental counterpart HuE71 IgG1, the afucosylated variant having enhanced Fc-receptor affinity showed high nonspecific uptake in lymph nodes. On the other hand, aglycosylated HuE71 IgG1 with abrogated Fc-receptor binding did not show lymphoid uptake. The use of the IgG4 subclass showed high nonspecific uptake in the kidneys, which was prevented by mutating serine at position 228 to proline in the hinge region of the IgG4 antibody to mitigate in vivo fragment antigen-binding arm exchange. Conclusion: Our findings highlight the influence of Fc modifications and the choice of IgG subclass on the in vivo biodistribution of antibodies and the potential outcomes thereof. Copyright © 2022 by the Society of Nuclear Medicine and Molecular Imaging. |
| Keywords: | mouse; animal; metabolism; animals; mice; monoclonal antibody; immunoglobulin g; nude mouse; tissue distribution; mice, nude; nerve cell adhesion molecule l1; neural cell adhesion molecule l1; immunoglobulin f(ab) fragment; immuno-pet; antibodies, monoclonal, humanized; immunoglobulin fab fragments; afucosylated antibody; aglycosylated antibody; fab arm exchange |
| Journal Title: | Journal of Nuclear Medicine |
| Volume: | 63 |
| Issue: | 4 |
| ISSN: | 0161-5505 |
| Publisher: | Society of Nuclear Medicine |
| Date Published: | 2022-04-01 |
| Start Page: | 629 |
| End Page: | 636 |
| Language: | English |
| DOI: | 10.2967/jnumed.121.262383 |
| PUBMED: | 34353869 |
| PROVIDER: | scopus |
| PMCID: | PMC8973293 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 May 2022 -- Source: Scopus |
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