RT Journal Article
SR Electronic
T1 Influence of Fc modifications and IgG subclass on biodistribution of humanized antibodies targeting L1CAM
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP jnumed.121.262383
DO 10.2967/jnumed.121.262383
A1 Sai Kiran Sharma
A1 Maya Suzuki
A1 Hong Xu
A1 Joshua A. Korsen
A1 Zachary Samuels
A1 Hongfen Guo
A1 Brandon Nemieboka
A1 Alessandra Piersigilli
A1 Kimberly J. Edwards
A1 Nai-Kong Cheung
A1 Jason S. Lewis
YR 2021
UL http://jnm.snmjournals.org/content/early/2021/08/05/jnumed.121.262383.abstract
AB Immuno-positron emission tomography (immuno-PET) is a powerful tool to noninvasively characterize the in vivo biodistribution of engineered antibodies (Abs). Methods: L1 cell adhesion molecule (L1CAM)-targeting HuE71 immunoglobulin G1 (IgG1) and immunoglobulin G4 (IgG4) Abs bearing identical variable heavy and light chain sequences but different fragment crystallizable (Fc) portions were radiolabeled with Zirconium-89 (89Zr) and the in vivo biodistribution was studied in SKOV3 ovarian cancer xenografted nude mice. Results: In addition to showing uptake in L1CAM-expressing SKOV3 tumors like its parental counterpart HuE71 IgG1, the afucosylated variant having enhanced Fc-receptor (FcR) affinity showed high nonspecific uptake in lymph nodes. On the other hand, aglycosylated HuE71 IgG1 with abrogated FcR binding did not show lymphoid uptake. The use of IgG4 subclass showed high nonspecific uptake in the kidneys, which was prevented by mutating serine at position 228 to proline (S228P) in the hinge region of the IgG4 Ab to mitigate in vivo fragment antigen-binding (Fab) arm exchange. Conclusion: Our findings highlight the influence of Fc-modifications and the choice of IgG subclass on the in vivo biodistribution of Abs and the potential outcomes thereof.