TY - JOUR
T1 - Influence of Fc Modifications and IgG Subclass on Biodistribution of Humanized Antibodies Targeting L1CAM
AU - Sharma, Sai Kiran
AU - Suzuki, Maya
AU - Xu, Hong
AU - Korsen, Joshua A.
AU - Samuels, Zachary
AU - Guo, Hongfen
AU - Nemieboka, Brandon
AU - Piersigilli, Alessandra
AU - Edwards, Kimberly J.
AU - Cheung, Nai Kong V.
AU - Lewis, Jason S.
N1 - Funding Information:
This work was supported by the MSKCC Small Animal Imaging Core, funded in part by NIH Small-Animal Imaging Research Program (SAIRP) grant R24 CA83084 and NIH center grant P30 CA08748 and by the Tri-Institutional Laboratory of Comparative Pathology, which was funded in part by NIH grant P30 CA08748. The work was also supported by an R01 CA176671 awarded to Jason Lewis and a diversity supplement R01 CA176671 awarded to Brandon Nemieboka. Brandon Nemieboka was supported by a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the National Institutes of Health under award number T32GM007739 to the Weill Cornell/ Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program. Jason Lewis was supported by R01 CA204167 and R35CA2 32130. Jason Lewis acknowledges funding support from the Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research and the Center for Experimental Therapeutics at Memorial Sloan Kettering Cancer Center. Sai Kiran Sharma acknowledges the Tow Foundation for a Postdoctoral Fellowship Award. Nai-Kong Cheung, Maya Suzuki, Brandon Nemieboka, Hong Xu, and Jason Lewis were named as inventors on the L1CAM patent (WO2018232188A1) filed by Memorial Sloan Kettering. Both Memorial Sloan Kettering and Nai-Kong Cheung have financial interest in Y-mAbs Therapeutics Inc., Abpro-Labs, and Eureka Therapeutics. Nai-Kong Cheung reports receiving commercial research grants from Y-mAbs Therapeutics Inc. and Abpro-Labs Inc. Nai-Kong Cheung was named as inventor on multiple patents filed by Memorial Sloan Kettering, including those licensed to Y-mAbs Therapeutics Inc., Biotec Pharmacon, and Abpro-labs. Nai-Kong Cheung is a Scientific Advisory Board member for Abpro-Labs and Eureka Therapeutics. Jason Lewis is an associate editor of The Journal of Nuclear Medicine but had no involvement or access to information regarding the peer review of this article. Sai Kiran Sharma is a member of the editorial board of The Journal of Nuclear Medicine.
Publisher Copyright:
Copyright © 2022 by the Society of Nuclear Medicine and Molecular Imaging.
PY - 2022/4/1
Y1 - 2022/4/1
N2 - 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.
AB - 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.
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U2 - 10.2967/jnumed.121.262383
DO - 10.2967/jnumed.121.262383
M3 - Article
C2 - 34353869
AN - SCOPUS:85128141739
SN - 0161-5505
VL - 63
SP - 629
EP - 636
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 4
ER -
