Maternofetal transplacental transport of recombinant IgG antibodies lacking effector functions
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Maternofetal transplacental transport of recombinant IgG antibodies lacking effector functions. / Mathiesen, Line; Nielsen, Leif K; Andersen, Jan Terje; Grevys, Algirdas; Sandlie, Inger; Michaelsen, Terje E; Hedegaard, Morten; Knudsen, Lisbeth E.; Dziegiel, Morten Hanefeld.
In: Blood, Vol. 122, No. 7, 10.07.2013, p. 1174-1181.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Maternofetal transplacental transport of recombinant IgG antibodies lacking effector functions
AU - Mathiesen, Line
AU - Nielsen, Leif K
AU - Andersen, Jan Terje
AU - Grevys, Algirdas
AU - Sandlie, Inger
AU - Michaelsen, Terje E
AU - Hedegaard, Morten
AU - Knudsen, Lisbeth E.
AU - Dziegiel, Morten Hanefeld
PY - 2013/7/10
Y1 - 2013/7/10
N2 - 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. Pathogenic maternal IgG antibodies will 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 non-destructive IgG antibody blocking antigen binding while retaining binding to FcRn. We report on two human IgG3 antibodies with a hinge deletion and a C131S point mutation (IgG3ΔHinge) that eliminate complement activation and binding to all classical Fcγ receptors (FcγRs) and to C1q while binding to FcRn is retained. Additionally, one of the antibodies has a single point mutation in the Fc (R435H) at the binding site for FcRn (IgG3ΔHinge: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: IgG3ΔHinge:R435H>wild type IgG1≥IgG3ΔHinge, and IgG3ΔHinge:R435H=wild type IgG1=wild type IgG3>IgG3ΔHinge, respectively. Collectively, IgG3ΔHinge:R435H was transported efficiently from the maternal to the fetal placental compartment. Thus, IgG3ΔHinge:R435H may be a good candidate for transplacental delivery of a non-destructive antibody to the fetus to combat pathogenic antibodies.
AB - 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. Pathogenic maternal IgG antibodies will 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 non-destructive IgG antibody blocking antigen binding while retaining binding to FcRn. We report on two human IgG3 antibodies with a hinge deletion and a C131S point mutation (IgG3ΔHinge) that eliminate complement activation and binding to all classical Fcγ receptors (FcγRs) and to C1q while binding to FcRn is retained. Additionally, one of the antibodies has a single point mutation in the Fc (R435H) at the binding site for FcRn (IgG3ΔHinge: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: IgG3ΔHinge:R435H>wild type IgG1≥IgG3ΔHinge, and IgG3ΔHinge:R435H=wild type IgG1=wild type IgG3>IgG3ΔHinge, respectively. Collectively, IgG3ΔHinge:R435H was transported efficiently from the maternal to the fetal placental compartment. Thus, IgG3ΔHinge:R435H may be a good candidate for transplacental delivery of a non-destructive antibody to the fetus to combat pathogenic antibodies.
U2 - 10.1182/blood-2012-12-473843
DO - 10.1182/blood-2012-12-473843
M3 - Journal article
C2 - 23843496
VL - 122
SP - 1174
EP - 1181
JO - Blood
JF - Blood
SN - 0006-4971
IS - 7
ER -
ID: 47553258