Maternofetal transplacental transport of recombinant IgG antibodies lacking effector functions

作者：Mathiesen Line; Nielsen Leif K; Andersen Jan Terje; Grevys Algirdas; Sandlie Inger; Michaelsen Terje E; Hedegaard Morten; Knudsen Li**eth E; Dziegiel Morten Hanefeld^*

来源：Blood, 2013, 122(7): 1174-1181.

DOI：10.1182/blood-2012-12-473843

The neonatal Fc receptor (FcRn) directs the transfer of maternal immunoglobulin G (IgG) antibodies across the placenta and thus provides the fetus and newborn with passive protective humoral immunity. Pathogenicmaternal IgGantibodieswill also be delivered via the placenta and can cause alloimmunity, which may be lethal. A novel strategy to control pathogenic antibodies would be administration of a nondestructive IgG antibody blocking antigen binding while retaining binding to FcRn. We report on 2 human IgG3 antibodies with a hinge deletion and a C131S pointmutation (IgG Delta DHinge) that eliminate complement activation and binding to all classical Fcg receptors (FcgRs) and to C1q while binding to FcRn is retained. Additionally, 1 of the antibodies has a single point mutation in the Fc (R435H) at the binding site for FcRn (IgG Delta DHinge: R435H). We compared transplacental transport with wild-type IgG1 and IgG3, and found transport across trophoblast-derived BeWo cells and ex vivo placenta perfusions with hierarchies as follows: IgG3DHinge: R435H> wild-type IgG1 IgG3DHinge and IgG Delta DHinge: R435H5wild-type IgG15wild-type IgG3>>> IgG3DHinge, respectively. Collectively, IgG3DHinge: R435H was transported efficiently from the maternal to the fetal placental compartment. Thus, IgG3DHinge: R435H may be a good candidate for transplacental delivery of a nondestructive antibody to the fetus to combat pathogenic antibodies.

• 出版日期2013-8-15