Monoclonal Antibody Clearance

The neonatal Fc receptor (FcRn) plays a critical role in regulating IgG homeostasis in vivo. There are mixed reports on whether modification of the interaction with FcRn can be used as an engineering strategy to improve the pharmacokinetic and pharmacodynamic properties of monoclonal antibodies. We tested whether the T250Q/M428L mutations, which improved the pharmacokinetics of humanized IgGs in the rhesus monkey, would translate to a pharmacokinetic benefit in both cynomolgus monkeys and mice when constructed on a different humanized IgG framework (anti-tumor necrosis factor-α (TNFα)). The T250Q/M428L anti-TNFα variant displayed an ∼40-fold increase in binding affinity to cynomolgus monkey FcRn (C-FcRn) at pH 6.0, with maintenance of the pH binding dependence. We also constructed another anti-TNFα variant (P257I/Q311I) whose binding kinetics with the C-FcRn was similar to that of the T250Q/M428L variant. The binding affinity of the T250Q/M428L variant for murine FcRn was increased ∼500-fold, with maintenance of pH dependence. In contrast to the interaction with C-FcRn, this interaction was driven mainly by a decrease in the rate of dissociation. Despite the improved in vitro binding properties of the anti-TNFα T250Q/M428L and P257I/Q311I variants to C-FcRn, the pharmacokinetic profiles of these molecules were not differentiated from the wild-type antibody in cynomolgus monkeys after intravenous administration. When administered intravenously to mice, the T250Q/M428L anti-TNFα variant displayed improved pharmacokinetics, characterized by an ∼2-fold slower clearance than the wild-type antibody. The discrepancy between these data and previously reported benefits in rhesus monkeys and the inability of these mutations to translate to improved kinetics across species may be related to a number of factors. We propose extending consideration to differences in the absolute IgG-FcRn affinity, the kinetics of the IgG/FcRn interaction, and differences in the relative involvement of this pathway in the context of other factors influencing the disposition or elimination of monoclonal antibodies. The neonatal Fc receptor (FcRn) plays a critical role in regulating IgG homeostasis in vivo. There are mixed reports on whether modification of the interaction with FcRn can be used as an engineering strategy to improve the pharmacokinetic and pharmacodynamic properties of monoclonal antibodies. We tested whether the T250Q/M428L mutations, which improved the pharmacokinetics of humanized IgGs in the rhesus monkey, would translate to a pharmacokinetic benefit in both cynomolgus monkeys and mice when constructed on a different humanized IgG framework (anti-tumor necrosis factor-α (TNFα)). The T250Q/M428L anti-TNFα variant displayed an ∼40-fold increase in binding affinity to cynomolgus monkey FcRn (C-FcRn) at pH 6.0, with maintenance of the pH binding dependence. We also constructed another anti-TNFα variant (P257I/Q311I) whose binding kinetics with the C-FcRn was similar to that of the T250Q/M428L variant. The binding affinity of the T250Q/M428L variant for murine FcRn was increased ∼500-fold, with maintenance of pH dependence. In contrast to the interaction with C-FcRn, this interaction was driven mainly by a decrease in the rate of dissociation. Despite the improved in vitro binding properties of the anti-TNFα T250Q/M428L and P257I/Q311I variants to C-FcRn, the pharmacokinetic profiles of these molecules were not differentiated from the wild-type antibody in cynomolgus monkeys after intravenous administration. When administered intravenously to mice, the T250Q/M428L anti-TNFα variant displayed improved pharmacokinetics, characterized by an ∼2-fold slower clearance than the wild-type antibody. The discrepancy between these data and previously reported benefits in rhesus monkeys and the inability of these mutations to translate to improved kinetics across species may be related to a number of factors. We propose extending consideration to differences in the absolute IgG-FcRn affinity, the kinetics of the IgG/FcRn interaction, and differences in the relative involvement of this pathway in the context of other factors influencing the disposition or elimination of monoclonal antibodies. Monoclonal antibodies (mAbs) 2The abbreviations used are: mAb, monoclonal antibodies; FcRn, neonatal Fc receptor; TNFα, anti-tumor necrosis factor-α; WT, wild type; C-FcRn, cynomolgus monkey FcRn; M-FcRn, murine FcRn; PBS, phosphate-buffered saline; SPR, surface plasmon resonance; ELISA, enzyme-linked immunosorbent assay; C-IgG, endogenous cynomolgus monkey IgG; M-IgG, endogenous murine IgG; LLOQ, lower limit of quantitation. and Fc fusion proteins have become important therapeutic options in numerous disease indications, including cancer, inflammation, and autoimmune diseases (1Kim S.J. Park Y. Hong H.J. Mol. Cells. 2005; 20: 17-29PubMed Google Scholar). The proven efficacy of these molecular entities in combination with advances in protein engineering and directed evolution strategies has led to efforts to optimize the functional activity of these biologic agents. The goal of many of these approaches is to improve patient convenience and safety by reducing dose and/or dose frequency and potentially to improve efficacy (1Kim S.J. Park Y. Hong H.J. Mol. Cells. 2005; 20: 17-29PubMed Google Scholar). Many reports have suggested that improvement in the pharmacokinetic and pharmacodynamic properties of humanized monoclonal antibodies may be gained through modification of the interaction of the Fc region of IgGs with FcRn (2Ghetie V. Popov S. Borvak J. Radu C. Matesoi D. Medesan C. Ober R.J. Ward E.S. Nat. Google C. S. J. Google S. J. Google C. D. V. Ward E.S. J. Google J. Mol. Google Scholar). has that the properties of the receptor interaction may the of IgGs in clearance and increased in R.J. C. J. Ward E.S. S. Google R.J. C. C. J. Ward E.S. J. Google E.S. J. V. Ober R.J. Google Scholar). these pharmacokinetic can translate to or therapeutic of a mAb, has of to of the IgG/FcRn interaction that can as the of a and protein engineering FcRn has to be in the of IgGs across of IgG from to Medesan C. V. Ward E.S. J. Google C. Ward E.S. Google C. Radu C. V. Ward E.S. J. Google J. Google Scholar). also to the role of FcRn in regulating of IgGs in and species (2Ghetie V. Popov S. Borvak J. Radu C. Matesoi D. Medesan C. Ober R.J. Ward E.S. Nat. Google E.S. J. V. Ober R.J. Google V. Y. Ward E.S. J. Google V. Ward E.S. Google S. Google Radu V. Ward E.S. J. Google Scholar). The of the IgG/FcRn is pH binding dependence. IgG can to FcRn the Fc region at pH 6.0, binding at and of the is also at pH J. Google Google Google J. Google Scholar). The pH of this interaction has as the for the of IgG and In is that that IgG the with IgG binding to FcRn in the of the R.J. C. J. Ward E.S. S. Google R.J. C. C. J. Ward E.S. J. Google E.S. J. V. Ober R.J. Google Scholar). antibody is to be from by a pathway to the surface the pH and of IgG the R.J. C. J. Ward E.S. S. Google R.J. C. C. J. Ward E.S. J. Google E.S. J. V. Ober R.J. Google Scholar). in is to be directed a pathway in in R.J. C. J. Ward E.S. S. Google R.J. C. C. J. Ward E.S. J. Google E.S. J. V. Ober R.J. Google Scholar). The of IgG through the is to be important in the of an IgG in the R.J. C. C. J. Ward E.S. J. Google Scholar). the of FcRn the of engineering strategies at the pharmacokinetic of an antibody has to increase the affinity of an IgG for FcRn at pH the pH of the interaction C. S. J. Google S. J. Google Y. J. Google Ward E.S. S. J. Google Scholar). in the and of IgG Fc have to be important to the pH of the IgG/FcRn binding interaction J. Mol. Google C. Radu C. V. Ward E.S. J. Google Radu V. Ward E.S. J. Google Ward E.S. S. J. Google V. Ward E.S. J. Google Google Google Scholar). of in this region has the of a number of to this interaction may antibody clearance and the in of therapeutic monoclonal antibodies (2Ghetie V. Popov S. Borvak J. Radu C. Matesoi D. Medesan C. Ober R.J. Ward E.S. Nat. Google C. S. J. Google S. J. Google C. D. V. Ward E.S. J. Google Y. J. Google Ward E.S. S. J. Google V. Ward E.S. J. Google Mol. Google Scholar). reports have suggested that Fc or mutations in the Fc region with an increase in the affinity of the IgG/FcRn interaction at pH to differences in the of these antibodies in (2Ghetie V. Popov S. Borvak J. Radu C. Matesoi D. Medesan C. Ober R.J. Ward E.S. Nat. Google C. S. J. Google S. J. Google C. D. V. Ward E.S. J. Google V. Ward E.S. J. Google Scholar). from a number of have data that to this whether a between FcRn affinity and in clearance Y. J. Google Ward E.S. S. J. Google Mol. Google Scholar). these the from these to this is the data that have on the of this receptor interaction to the in properties of an antibody in reports have that mutations and are to the T250Q/M428L of both to and to of to to and to P257I/Q311I of both to and to of to to a humanized and/or which increased affinity for FcRn at pH 6.0, in a elimination in cynomolgus or rhesus monkeys C. S. J. Google S. J. Google J. Google Scholar). In a Fc mutations that similar affinity and in vitro binding properties to a humanized not translate to in benefit in cynomolgus monkeys Y. J. Google Scholar). these data not the that a engineering strategy to the in kinetics of a of antibody can be on of the IgG/FcRn In this tested whether the Fc which previously to improve the pharmacokinetic properties of humanized IgGs in the rhesus monkey, would translate to a similar benefit when constructed on a different IgG Fc variants were on an anti-TNFα antibody with the of the of binding on the kinetics or of the antibody. We constructed the anti-TNFα T250Q/M428L variant with a anti-TNFα are to the T250Q/M428L of both to and to of to to and to P257I/Q311I of both to and to of to The T250Q/M428L mutations in an increased pH binding affinity, with maintenance of pH binding in a similar to that reported previously C. S. J. Google S. J. Google Scholar). In the in vitro binding of the anti-TNFα P257I/Q311I variant were and similar to that of the anti-TNFα T250Q/M428L variant. the pharmacokinetic profiles of the anti-TNFα T250Q/M428L and P257I/Q311I were not differentiated from the wild-type anti-TNFα after intravenous to cynomolgus that engineering strategies to improve the in of an IgG to the FcRn interaction in context with other factors and which may the disposition or elimination of a monoclonal antibody were at in with and and of P257I/Q311I antibody variant was from a humanized Fc variant a strategy Google for other anti-TNFα Fc variants Y. J. Google Scholar). The T250Q/M428L variant was by of the anti-TNFα the and by The WT, and T250Q/M428L anti-TNFα IgGs were in and from protein affinity by previously for other anti-TNFα antibodies Y. J. Google Scholar). cynomolgus monkey FcRn (C-FcRn) and murine FcRn were in with the for the of receptor species and and the proteins were as previously Y. J. Google Scholar). of and protein and protein were used to IgG from of cynomolgus monkey and protein and to IgG in the were with of protein or protein for of or or was to the by The were with the to antibodies were with and were of of the antibodies were and characterized by reducing that the IgGs from both species were to than and displayed the and for The IgGs were PBS, and the were and at of the IgG in and IgG in cynomolgus monkey and were by from the used in the pharmacokinetic for the IgG in or of an was at with of IgG or IgG and and were to the in a of and for at of cynomolgus monkey or were in in to to the and monkey IgGs were IgG and IgG The IgG murine and were used to for the of endogenous IgG in mice and cynomolgus The for both the and murine displayed was with the used for or The of endogenous murine and cynomolgus monkey IgG was also by the at and an of for The endogenous murine and cynomolgus IgG by and were the used to the IgG with the murine and cynomolgus monkey IgG/FcRn with interaction of anti-TNFα and the P257I/Q311I and T250Q/M428L variants with C-FcRn, and was by surface plasmon a as previously Y. J. Google Scholar). The with endogenous and endogenous were characterized in the In C-FcRn, and were to and of a The surface of receptor species was The was used as a surface FcRn and was to the other Y. J. Google Scholar). binding were with the and Fc variant IgGs in a of to as for Y. J. Google Scholar). The binding data were by the of from the other binding were through of the of data on The kinetics and were to a binding to the for interaction Google Scholar). The data for of the and for the WT, and T250Q/M428L C-FcRn and for were by protein with the by the and the was as and the The for the interaction of receptor species with the WT, and T250Q/M428L anti-TNFα antibodies was as in with other variant anti-TNFα IgGs Y. J. Google Scholar). data were by the as previously Y. J. Google to the of the of the pH at which of the data are as the of the antibody at pH cynomolgus monkey pharmacokinetic were In both cynomolgus monkeys were to of In the a intravenous dose of anti-TNFα or P257I/Q311I in at In the a intravenous dose of anti-TNFα or T250Q/M428L in at both were from the to and at and after of the were to at to to with anti-TNFα and T250Q/M428L were also in mice intravenous dose of the anti-TNFα or T250Q/M428L in was administered the at a dose of were from or at and after administration. The were by or by as and to and of the anti-TNFα and the P257I/Q311I and T250Q/M428L variants in cynomolgus monkey and were and/or previously Y. J. Google Scholar). The and T250Q/M428L were in cynomolgus monkey or a of to The lower limit of was as The P257I/Q311I variant were to the other a from to The was as The and for antibody was the for both were the data were a on the The the the from to of and elimination differences in pharmacokinetic for the wild-type and Fc variants in cynomolgus monkey were of In vitro binding data and were also of a mixed was which and for as of the and Fc with binding were for the interaction of the and Fc variant anti-TNFα antibodies with species of FcRn including the binding at pH and the interaction kinetics at pH and the pH of IgG from receptor and of the humanized anti-TNFα antibodies with were reported previously were reported previously data from of binding are with wild are with wild of the is at pH at which of the is as from a of the pH of the antibody in that at pH as by are with wild were reported previously Y. J. Google data from of binding are with wild of the is at pH pH at which of the is as from a of the of the antibody in that at pH as by in a of the humanized anti-TNFα antibodies with were reported previously were reported previously data from of binding are with wild are with wild of the IgG-FcRn is at pH at which of the is as from a of the are with wild are with wild pH of the antibody in that at pH as by were reported previously Y. J. Google data from of binding are with wild of the IgG-FcRn is at pH pH at which of the is as from a of the of the antibody in that at pH as by in a We the binding affinity and with and a of surface FcRn to on the interaction Y. J. Google Scholar). The T250Q/M428L variant with C-FcRn and at pH are and are of the P257I/Q311I variant. for the of the anti-TNFα were in Y. J. Google Scholar). The rate and for the interaction of the anti-TNFα IgGs with C-FcRn and were with a binding reported previously Google Scholar). We previously reported the binding affinity of the and P257I/Q311I antibodies for C-FcRn and Y. J. Google Scholar). The of the interaction with C-FcRn and was and and The T250Q/M428L and P257I/Q311I variants an increase in affinity to C-FcRn at pH of and relative to the WT, The T250Q/M428L and P257I/Q311I variant also displayed and in binding affinity to relative to the and data from has that IgGs in that not from FcRn are from the We this in vitro by at pH and the of of the to pH an previously Y. J. Google Scholar). The and and of the interaction as by the and the of antibody that to C-FcRn at pH and The of these were and the of antibody that to C-FcRn was The of and the T250Q/M428L variant with with of and the of the and T250Q/M428L IgGs from the at pH the antibody have different The at which the of P257I/Q311I with with a pH with at pH and the P257I/Q311I variant in the and the murine in are not in this The affinity of the variants for C-FcRn relative to the were driven by increased kinetics with on of In the increased affinity of the T250Q/M428L variant for at pH was to a slower rate of The increased affinity of P257I/Q311I variant was to on both the rate of and The improved affinity of these variant IgG is with reports the involvement of the and Fc in the interaction of IgG with FcRn J. Mol. Google C. Radu C. V. Ward E.S. J. Google Radu V. Ward E.S. J. Google Google Y. J. Google Ward E.S. S. J. Google Google Google Google Mol. Google Hong J. J. D. J. J. Google Google Google Scholar). the IgG tested for pH binding the variant anti-TNFα at to species of FcRn at pH not that these mutations not the pH binding of the interaction Ward E.S. S. J. Google Scholar). IgG and for of the of endogenous IgG and binding for FcRn has not in to engineering strategies at the pharmacokinetic properties of therapeutic through the FcRn these factors may to species differences in in properties of a or binding to The of endogenous IgG in the of cynomolgus monkeys and mice were to be and by affinity from or the binding affinity and interaction kinetics of the and were with C-FcRn and M-FcRn, The C-FcRn with an affinity of which is ∼2-fold than that of the anti-TNFα interaction with C-FcRn and The was also of and and slower than the anti-TNFα antibody and In the variant IgGs C-FcRn with affinity than C-IgG, the kinetics of the were than for the interaction and of endogenous cynomolgus monkey IgG and murine IgG with species IgG in or was by data from of binding of the is at pH IgG in or was by data from of binding of the is at pH in a to with an affinity of which is ∼2-fold than the affinity of anti-TNFα for to the interaction, the also and kinetics relative to the The anti-TNFα variants with affinity than the the P257I/Q311I variant an increase in affinity for relative to M-IgG, driven by an increased rate of The T250Q/M428L variant to with an affinity than to by both an increased rate and rate of and Fc in relative improvement in FcRn binding affinity to the anti-TNFα by the T250Q/M428L mutations was similar to that reported previously with a different monoclonal antibody C. S. J. Google S. J. Google Scholar). We also a similar affinity and on binding kinetics with a of mutations of the of the T250Q/M428L mutations on in vitro affinity, to the in C. S. J. Google S. J. Google that these mutations in pharmacokinetic benefit when to a of antibody the also to the in of P257I/Q311I mutations, which in similar in vitro FcRn binding as T250Q/M428L these the pharmacokinetics of the variants and the anti-TNFα in cynomolgus intravenous of or the and variant were from the in a The profiles of the and variant were similar to other differences were between the and variant antibodies in of or The antibody a elimination of and the P257I/Q311I and T250Q/M428L variants a of and The for the and Fc variants were similar of whether were the or that is that the kinetics of these antibodies were by or by with the for humanized anti-TNFα and the P257I/Q311I and T250Q/M428L variants in cynomolgus monkeys after intravenous were reported previously were reported previously Y. J. Google Scholar). in a of and T250Q/M428L in pharmacokinetic of the anti-TNFα and T250Q/M428L variant was in mice to whether the differences in the in vitro binding with with improved kinetics The and T250Q/M428L anti-TNFα antibodies were administered as a intravenous dose of The antibodies were from the in a were in the clearance and of of the antibodies The clearance of the T250Q/M428L variant was slower and ∼2-fold than the The of the and variant antibody was for the humanized anti-TNFα and the T250Q/M428L variant in mice after intravenous of in a in FcRn mice have the role of the FcRn receptor in regulating the of endogenous and administered IgG V. Y. Ward E.S. J. Google S. J. J. Google J. Google Scholar). In mutations in the Fc region that binding of IgG to FcRn increase the clearance of an IgG in Radu V. Ward E.S. J. Google Radu C. Ober R.J. D. V. Ward E.S. Google Scholar). a these this receptor interaction an by which to therapeutic antibodies for improved pharmacokinetic and pharmacodynamic data that or the of this receptor pathway to a on the clearance and of antibodies V. Y. Ward E.S. J. Google S. J. J. Google J. Google C. J. Ober R.J. Ward E.S. Nat. 2005; Google J. C. S. S. Google Scholar). reported in the that this receptor can be used as an to improve the in pharmacokinetic properties of an IgG Y. J. Google Ward E.S. S. J. Google Mol. Google Scholar). In this to or a is important to translate in to that of a species as the role of FcRn in regulating IgG or the of Fc engineering on IgG pharmacokinetics in In C. S. J. Google S. J. Google a and and the Fc region of a humanized and mutations in improved pharmacokinetic characterized by a slower clearance and increased when administered to rhesus monkeys by intravenous The molecules with the T250Q/M428L binding of relative to the a binding with FcRn at pH C. S. J. Google S. J. Google Scholar). The binding of in vitro and a similar pharmacokinetic as the T250Q/M428L variant in the rhesus monkey tested on an the of was not tested in C. S. J. Google Scholar). In both the and T250Q/M428L variants the pH of binding and C. S. J. Google Scholar). led to the that a of and Fc fusion proteins be to have by of this to these molecules C. S. J. Google Scholar). of the T250Q/M428L mutations to anti-TNFα also a increase in FcRn binding at pH with maintenance of the pH of binding and were not to pharmacokinetic benefit in cynomolgus monkeys and a anti-TNFα variant (P257I/Q311I) that the of increase in in vitro affinity and binding as the anti-TNFα T250Q/M428L variant not pharmacokinetic benefit in cynomolgus monkeys and with the that the affinity of an IgG for FcRn at pH to improved in The data that the in benefit from the T250Q/M428L is not to other In these the that a of mutations can be used to pharmacokinetic benefit to a of therapeutic antibodies. is not as to Fc mutations that similar in vitro FcRn binding to an IgG not in similar to in pharmacokinetic In the in clearance and elimination of the anti-TNFα in cynomolgus monkeys were and than that for the in rhesus monkeys C. S. J. Google and be related to differences in in the clearance and elimination of these antibodies. for the discrepancy in the of the Fc is that FcRn is of or is not the in regulating the clearance of the anti-TNFα in In the other the clearance of a mAb, is that in FcRn binding affinity may not in on in the other the in properties of or another were to a role of FcRn in may be to that receptor the anti-TNFα and a in the than in and this would also be with the of the T250Q/M428L anti-TNFα on in clearance in mice and that is to differences in the or of the or variant anti-TNFα molecules that potentially clearance not is not be in clearance in the as a in J. Google C. J. Google S. Google is that clearance is driven by binding to or clearance of the that a binding to the clearance of the anti-TNFα in and the benefit of improved FcRn binding be The of data with other Y. J. Google Ward E.S. S. J. Google Mol. Google at from an antibody engineering a between FcRn binding affinity and improved in properties is to In this of other as the mutations J. Google that have to pharmacokinetic improvement to IgG is In to the mutations, a humanized Fc an FcRn binding affinity relative to the at pH J. Google Scholar). the increase in binding affinity of for the receptor was than that reported previously for other IgG variants Y. J. Google Ward E.S. S. J. Google the increase of for this variant IgG the in benefit in the J. Google Scholar). the in these reports C. S. J. Google S. J. Google Y. J. Google Ward E.S. S. J. Google J. Google that of antibody clearance may be influencing the in of engineering strategies at the IgG/FcRn the of pharmacokinetic is in the of the and T250Q/M428L variants of were also from other a in for rhesus FcRn C. S. J. Google Scholar). the of Fc mutations that affinity of FcRn binding to translate to improved in properties may also be related to the affinity of an Fc for In this the anti-TNFα was to have a of similar to the that has reported for the binding of other IgGs to FcRn Y. J. Google Ward E.S. S. J. Google Hong J. J. D. J. J. Google J. C. S. S. Google Scholar). is that relative to the affinity the binding are not to the in of this in The in kinetics in the rhesus monkey, which be with a affinity for the of or variants of for rhesus monkey FcRn were not reported of the C. S. J. Google S. J. Google Scholar). the FcRn binding affinity was reported for the FcRn binding kinetics were not J. Google Scholar). is to the the binding affinity for in the in the context of of the differences in the J. Google Scholar). In to increased affinity, that a similar binding increase translate to improved pharmacokinetic FcRn was the of would not be with the binding affinity to translate to the in benefit with the T250Q/M428L anti-TNFα variant in mice The of the absolute affinity of an IgG for FcRn is also important to in the context of the of endogenous IgGs and relative FcRn binding In cynomolgus monkey, that the endogenous IgGs an affinity for FcRn that was ∼2-fold than that of the anti-TNFα mAb, and the were to be in the of In the endogenous IgG are in at may be to the in with the of affinity In the endogenous murine IgG an affinity for relative to that of the anti-TNFα mAb, and were to be the of that the lower endogenous IgG with the lower FcRn affinity in mice would of in benefit in combination with the affinity improvement of the T250Q/M428L anti-TNFα variant the P257I/Q311I displayed increased affinity for M-FcRn, was from the in mice of of at pH FcRn Y. J. Google Scholar). the of FcRn on the in of an may also be important to the interaction of IgG and FcRn in of Y. J. Google Scholar). In combination with affinity, the rate of of the after at pH may be a the of through the or the and related to in In the of the variant anti-TNFα the improved for C-FcRn was a of in rate with in of The differences in the rate of the variant and anti-TNFα may not be to in in pharmacokinetic binding kinetics were not is to whether the or rate was by the T250Q/M428L mutations in C. S. J. Google S. J. Google Scholar). the T250Q/M428L mutations were to a similar of in when on an and for is to that with similar in affinity were similar on the kinetics of and dissociation. is not mutations that similar binding pH to would the and is also that affinity or differences be driven through of different In the in this that may be to a of that can be used to the of the pharmacokinetic properties of a of therapeutic monoclonal antibodies. both the of the antibody affinity, and therapeutic or can disposition and is that many factors in to antibody to be when engineering We and for the of FcRn and anti-TNFα for with of the anti-TNFα and for the of the and and for