PMID- 25220345
OWN - NLM
STAT- MEDLINE
DCOM- 20150204
LR  - 20211021
IS  - 1096-0945 (Electronic)
IS  - 0014-4800 (Print)
IS  - 0014-4800 (Linking)
VI  - 97
IP  - 3
DP  - 2014 Dec
TI  - A new bispecific antibody targeting non-overlapping epitopes on IGF2: design, in 
      vitro characterization and pharmacokinetics in macaques.
PG  - 359-67
LID - S0014-4800(14)00148-8 [pii]
LID - 10.1016/j.yexmp.2014.09.007 [doi]
AB  - The insulin-like growth factor 2 (IGF2) is an important target for cancer 
      therapy. We have previously proposed an approach for fast and irreversible 
      removal of IGF2 from the circulation by using monoclonal antibodies (mAbs) that 
      bind to two or more non-overlapping epitopes on the same molecule. We provided 
      initial evidence for the formation of oligomeric antibody-ligand complexes that 
      can bind to cells expressing Fc gamma receptors (FcgammaRs) with high avidity using 
      an antibody domain with relatively low affinity as one of the anti-IGF2 mAbs. 
      Recently, we identified a mAb, m708.5, in a scFv format which binds to both IGF2 
      and IGF1 with very high (pM) affinity. Interestingly, and rather surprisingly, 
      this mAb did not compete with our other high affinity mAb, m610.27, for binding 
      to IGF2. Therefore, we generated a new bispecific mAb, m67, by combining m708.5 
      and m610.27. As expected m67 potently inhibited binding of IGF2 to cells 
      expressing the IGF1R and its phosphorylation, and resulted in formation of 
      multimolecular complexes when incubated with IGF2 and bound with high avidity to 
      cells expressing FcgammaRII; the complexes were internalized in a macrophage-like 
      cell line. However, although m67 exhibited a reasonably long half-life (6.4 +/- 0.6 
      days) in cynomolgus macaques and high stability in serum, its administration to 
      three animals did not result in any measurable decrease in the IGF2 concentration 
      likely due to the complexity of the IGF2 interactions in the blood and the 
      relatively low (2mg/kg) dose of the mAb leading to a relatively low maximal blood 
      concentration of 120nM. In spite of the lack of effect on the IGF2 concentration 
      in this particular experimental setup, m67 exhibited good drugability properties 
      and could be highly effective in other animal models and in humans. Studies with 
      animal models of cancer are ongoing to evaluate the potential of m67 as a new 
      candidate mAb-based therapeutic.
CI  - Published by Elsevier Inc.
FAU - Feng, Yang
AU  - Feng Y
AD  - Protein Interactions Group, Cancer and Inflammation Program, Center for Cancer 
      Research, National Cancer Institute, Frederick, MD 21702, United States. 
      Electronic address: fengya@mail.nih.gov.
FAU - Zhao, Qi
AU  - Zhao Q
AD  - Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Guangdong 
      518000, China.
FAU - Chen, Weizao
AU  - Chen W
AD  - Protein Interactions Group, Cancer and Inflammation Program, Center for Cancer 
      Research, National Cancer Institute, Frederick, MD 21702, United States.
FAU - Wang, Yanping
AU  - Wang Y
AD  - Protein Interactions Group, Cancer and Inflammation Program, Center for Cancer 
      Research, National Cancer Institute, Frederick, MD 21702, United States; Geneva 
      Foundation, 917 Pacific Ave, Suite 600, Tacoma, WA 98402, United States.
FAU - Crowder, Karalyne
AU  - Crowder K
AD  - SNBL USA, 6605 Merrill Creek Parkway, Everett, WA 98203, United States.
FAU - Dimitrov, Dimiter S
AU  - Dimitrov DS
AD  - Protein Interactions Group, Cancer and Inflammation Program, Center for Cancer 
      Research, National Cancer Institute, Frederick, MD 21702, United States.
LA  - eng
GR  - Z99 CA999999/Intramural NIH HHS/United States
GR  - N01-CO-12400/CO/NCI NIH HHS/United States
GR  - HHSN261200800001E/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
DEP - 20140916
PL  - Netherlands
TA  - Exp Mol Pathol
JT  - Experimental and molecular pathology
JID - 0370711
RN  - 0 (Antibodies, Bispecific)
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Epitopes)
RN  - 0 (Epitopes, B-Lymphocyte)
RN  - 67763-97-7 (Insulin-Like Growth Factor II)
SB  - IM
MH  - Animals
MH  - Antibodies, Bispecific/immunology/*pharmacokinetics
MH  - Antibodies, Monoclonal/immunology/*pharmacokinetics
MH  - Antibody Specificity/*immunology
MH  - Antineoplastic Agents/immunology/*pharmacokinetics
MH  - Drug Design
MH  - Drug Stability
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Epitopes/immunology
MH  - Epitopes, B-Lymphocyte/immunology
MH  - Female
MH  - Flow Cytometry
MH  - Humans
MH  - Insulin-Like Growth Factor II/*antagonists & inhibitors/immunology
MH  - MCF-7 Cells
MH  - Macaca fascicularis
PMC - PMC4262567
MID - NIHMS632796
OTO - NOTNLM
OT  - Bispecific antibodies
OT  - Cynomolgus macaques
OT  - Half-life
OT  - IGF ligand
COIS- Conflict of Interest statement The authors declare that there are no conflicts of 
      interest.
EDAT- 2014/09/16 06:00
MHDA- 2015/02/05 06:00
PMCR- 2015/12/01
CRDT- 2014/09/16 06:00
PHST- 2014/09/10 00:00 [received]
PHST- 2014/09/11 00:00 [accepted]
PHST- 2014/09/16 06:00 [entrez]
PHST- 2014/09/16 06:00 [pubmed]
PHST- 2015/02/05 06:00 [medline]
PHST- 2015/12/01 00:00 [pmc-release]
AID - S0014-4800(14)00148-8 [pii]
AID - 10.1016/j.yexmp.2014.09.007 [doi]
PST - ppublish
SO  - Exp Mol Pathol. 2014 Dec;97(3):359-67. doi: 10.1016/j.yexmp.2014.09.007. Epub 
      2014 Sep 16.