Influence of Fc Modifications and IgG Subclass on Biodistribution of Humanized Antibodies Targeting L1CAM.
Where this comes from
- Record sourced from PubMed, PMID 34353869.
- Also identified by DOI 10.2967/jnumed.121.262383 and PMC identifier 8973293.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Immuno-PET is a powerful tool to noninvasively characterize the in vivo biodistribution of engineered antibodies. <b>Methods:</b> L1 cell adhesion molecule-targeting humanized (HuE71) IgG<sub>1</sub> and IgG<sub>4</sub> antibodies bearing identical variable heavy- and light-chain sequences but different fragment crystallizable (Fc) portions were radiolabeled with <sup>89</sup>Zr, and the in vivo biodistribution was studied in SKOV3 ovarian cancer xenografted nude mice. <b>Results:</b> In addition to showing uptake in L1 cell adhesion molecule-expressing SKOV3 tumors, as does its parental counterpart HuE71 IgG<sub>1</sub>, the afucosylated variant having enhanced Fc-receptor affinity showed high nonspecific uptake in lymph nodes. On the other hand, aglycosylated HuE71 IgG<sub>1</sub> with abrogated Fc-receptor binding did not show lymphoid uptake. The use of the IgG<sub>4</sub> 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 IgG<sub>4</sub> antibody to mitigate in vivo fragment antigen-binding arm exchange. <b>Conclusion:</b> 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.
Medical subject headings
- Antibodies, Monoclonal, Humanized
- Neural Cell Adhesion Molecule L1