Influence of Fc Modifications and IgG Subclass on Biodistribution of Humanized Antibodies Targeting L1CAM

Sai Kiran Sharma, Maya Suzuki, Hong Xu, Joshua A. Korsen, Zachary Samuels, Hongfen Guo, Brandon Nemieboka, Alessandra Piersigilli, Kimberly J. Edwards, Nai Kong V. Cheung, Jason S. Lewis

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)629-636
Number of pages8
JournalJournal of Nuclear Medicine
Volume63
Issue number4
DOIs
Publication statusPublished - Apr 1 2022

All Science Journal Classification (ASJC) codes

  • Radiology Nuclear Medicine and imaging

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