PMID- 26496237
OWN - NLM
STAT- MEDLINE
DCOM- 20160930
LR  - 20231111
IS  - 1942-0870 (Electronic)
IS  - 1942-0862 (Print)
IS  - 1942-0862 (Linking)
VI  - 8
IP  - 1
DP  - 2016
TI  - Calcium-dependent antigen binding as a novel modality for antibody recycling by 
      endosomal antigen dissociation.
PG  - 65-73
LID - 10.1080/19420862.2015.1110660 [doi]
AB  - The pH-dependent antigen binding antibody, termed a recycling antibody, has 
      recently been reported as an attractive type of second-generation engineered 
      therapeutic antibody. A recycling antibody can dissociate antigen in the acidic 
      endosome, and thus bind to its antigen multiple times. As a consequence, a 
      recycling antibody can neutralize large amounts of antigen in plasma. Because 
      this approach relies on histidine residues to achieve pH-dependent antigen 
      binding, which could limit the epitopes that can be targeted and affect the rate 
      of antigen dissociation in the endosome, we explored an alternative approach for 
      generating recycling antibodies. Since calcium ion concentration is known to be 
      lower in endosome than in plasma, we hypothesized that an antibody with 
      antigen-binding properties that are calcium-dependent could be used as recycling 
      antibody. Here, we report a novel anti-interleukin-6 receptor (IL-6R) antibody, 
      identified from a phage library that binds to IL-6R only in the presence of a 
      calcium ion. Thermal dynamics and a crystal structure study revealed that the 
      calcium ion binds to the heavy chain CDR3 region (HCDR3), which changes and 
      possibly stabilizes the structure of HCDR3 to make it bind to antigen calcium 
      dependently (PDB 5AZE). In vitro and in vivo studies confirmed that this 
      calcium-dependent antigen-binding antibody can dissociate its antigen in the 
      endosome and accelerate antigen clearance from plasma, making it a novel approach 
      for generating recycling antibody.
FAU - Hironiwa, N
AU  - Hironiwa N
AD  - a Research Division ; Chugai Pharmaceutical Co., Ltd. ; Tokyo , Japan.
FAU - Ishii, S
AU  - Ishii S
AD  - a Research Division ; Chugai Pharmaceutical Co., Ltd. ; Tokyo , Japan.
FAU - Kadono, S
AU  - Kadono S
AD  - a Research Division ; Chugai Pharmaceutical Co., Ltd. ; Tokyo , Japan.
FAU - Iwayanagi, Y
AU  - Iwayanagi Y
AD  - a Research Division ; Chugai Pharmaceutical Co., Ltd. ; Tokyo , Japan.
FAU - Mimoto, F
AU  - Mimoto F
AD  - a Research Division ; Chugai Pharmaceutical Co., Ltd. ; Tokyo , Japan.
FAU - Habu, K
AU  - Habu K
AD  - a Research Division ; Chugai Pharmaceutical Co., Ltd. ; Tokyo , Japan.
FAU - Igawa, T
AU  - Igawa T
AD  - a Research Division ; Chugai Pharmaceutical Co., Ltd. ; Tokyo , Japan.
FAU - Hattori, K
AU  - Hattori K
AD  - a Research Division ; Chugai Pharmaceutical Co., Ltd. ; Tokyo , Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151023
PL  - United States
TA  - MAbs
JT  - mAbs
JID - 101479829
RN  - 0 (Antigens)
RN  - 0 (Complementarity Determining Regions)
RN  - 0 (IL6R protein, human)
RN  - 0 (Receptors, Interleukin-6)
RN  - 0 (Single-Chain Antibodies)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - *Antigens/chemistry/metabolism
MH  - *Calcium/chemistry/metabolism
MH  - Cell Line
MH  - Complementarity Determining Regions/chemistry/metabolism
MH  - *Endosomes/chemistry/metabolism
MH  - Humans
MH  - Hydrogen-Ion Concentration
MH  - *Receptors, Interleukin-6/chemistry/metabolism
MH  - *Single-Chain Antibodies/chemistry/metabolism
PMC - PMC4966519
OTO - NOTNLM
OT  - Antibody engineering
OT  - antigen clearance
OT  - antigen dissociation
OT  - calcium ion
OT  - recycling antibody
EDAT- 2015/10/27 06:00
MHDA- 2016/10/01 06:00
PMCR- 2015/10/23
CRDT- 2015/10/27 06:00
PHST- 2015/10/27 06:00 [entrez]
PHST- 2015/10/27 06:00 [pubmed]
PHST- 2016/10/01 06:00 [medline]
PHST- 2015/10/23 00:00 [pmc-release]
AID - 1110660 [pii]
AID - 10.1080/19420862.2015.1110660 [doi]
PST - ppublish
SO  - MAbs. 2016;8(1):65-73. doi: 10.1080/19420862.2015.1110660. Epub 2015 Oct 23.