PMID- 24492343
OWN - NLM
STAT- MEDLINE
DCOM- 20150113
LR  - 20211021
IS  - 1942-0870 (Electronic)
IS  - 1942-0862 (Print)
IS  - 1942-0862 (Linking)
VI  - 5
IP  - 6
DP  - 2013 Nov-Dec
TI  - Effects of altered FcgammaR binding on antibody pharmacokinetics in cynomolgus 
      monkeys.
PG  - 896-903
LID - 10.4161/mabs.26436 [doi]
AB  - Antibody interactions with Fcgamma receptors (FcgammaRs), like FcgammaRIIIA, play a critical 
      role in mediating antibody effector functions and thereby contribute 
      significantly to the biologic and therapeutic activity of antibodies. Over the 
      past decade, considerable work has been directed towards production of antibodies 
      with altered binding affinity to FcgammaRs and evaluation of how the alterations 
      modulate their therapeutic activity. This has been achieved by altering 
      glycosylation status at N297 or by engineering modifications in the 
      crystallizable fragment (Fc) region. While the effects of these modifications on 
      biologic activity and efficacy have been examined, few studies have been 
      conducted to understand their effect on antibody pharmacokinetics (PK). We 
      present here a retrospective analysis in which we characterize the PK of three 
      antibody variants with decreased FcgammaR binding affinity caused by amino acid 
      substitutions in the Fc region (N297A, N297G, and L234A/L235A) and three antibody 
      variants with increased FcgammaRIIIA binding affinity caused by afucosylation at 
      N297, and compare their PK to corresponding wild type antibody PK in cynomolgus 
      monkeys. For all antibodies, PK was examined at a dose that was known to be in 
      the linear range. Since production of the N297A and N297G variants in Chinese 
      hamster ovary cells results in aglycosylated antibodies that do not bind to 
      FcgammaRs, we also examined the effect of expression of an aglycosylated antibody, 
      without sequence change(s), in E. coli. All the variants demonstrated similar PK 
      compared with that of the wild type antibodies, suggesting that, for the six 
      antibodies presented here, altered FcgammaR binding affinity does not affect PK.
FAU - Leabman, Maya K
AU  - Leabman MK
AD  - Department of Pharmacokinetics and Pharmacodynamics; Genentech, Inc; San 
      Francisco, CA USA.
FAU - Meng, Y Gloria
AU  - Meng YG
AD  - Department of Biochemical and Cellular Pharmacology; Genentech, Inc; San 
      Francisco, CA USA.
FAU - Kelley, Robert F
AU  - Kelley RF
AD  - Department of Antibody Engineering; Genentech, Inc; San Francisco, CA USA.
FAU - DeForge, Laura E
AU  - DeForge LE
AD  - Department of Biochemical and Cellular Pharmacology; Genentech, Inc; San 
      Francisco, CA USA.
FAU - Cowan, Kyra J
AU  - Cowan KJ
AD  - Department of BioAnalytical Sciences; Genentech, Inc; San Francisco, CA USA.
FAU - Iyer, Suhasini
AU  - Iyer S
AD  - Department of Pharmacokinetics and Pharmacodynamics; Genentech, Inc; San 
      Francisco, CA USA.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - MAbs
JT  - mAbs
JID - 101479829
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Receptors, Fc)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/genetics/metabolism/*pharmacokinetics
MH  - Cricetinae
MH  - Dose-Response Relationship, Drug
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Genetic Variation
MH  - Macaca fascicularis
MH  - Protein Binding
MH  - Receptors, Fc/*metabolism
PMC - PMC3896603
OTO - NOTNLM
OT  - FcgammaR binding
OT  - afucosylation
OT  - aglycosylation
OT  - antibody
OT  - pharmacokinetics
EDAT- 2014/02/05 06:00
MHDA- 2015/01/15 06:00
PMCR- 2014/11/01
CRDT- 2014/02/05 06:00
PHST- 2014/02/05 06:00 [entrez]
PHST- 2014/02/05 06:00 [pubmed]
PHST- 2015/01/15 06:00 [medline]
PHST- 2014/11/01 00:00 [pmc-release]
AID - 26436 [pii]
AID - 2013MABS0402R [pii]
AID - 10.4161/mabs.26436 [doi]
PST - ppublish
SO  - MAbs. 2013 Nov-Dec;5(6):896-903. doi: 10.4161/mabs.26436.