PMID- 20065654
OWN - NLM
STAT- MEDLINE
DCOM- 20100614
LR  - 20211020
IS  - 1942-0870 (Electronic)
IS  - 1942-0862 (Print)
IS  - 1942-0862 (Linking)
VI  - 2
IP  - 1
DP  - 2010 Jan-Feb
TI  - A dual-targeting PDGFRbeta/VEGF-A molecule assembled from stable antibody 
      fragments demonstrates anti-angiogenic activity in vitro and in vivo.
PG  - 20-34
AB  - Targeting angiogenesis is a promising approach to the treatment of solid tumors 
      and age-related macular degeneration (AMD). Inhibition of vascularization has 
      been validated by the successful marketing of monoclonal antibodies (mAbs) that 
      target specific growth factors or their receptors, but there is considerable room 
      for improvement in existing therapies. Combination of mAbs targeting both the 
      VEGF and PDGF pathways has the potential to increase the efficacy of 
      anti-angiogenic therapy without the accompanying toxicities of tyrosine kinase 
      inhibitors and the inability to combine efficiently with traditional 
      chemotherapeutics. However, development costs and regulatory issues have limited 
      the use of combinatorial approaches for the generation of more efficacious 
      treatments. The concept of mediating disease pathology by targeting two antigens 
      with one therapeutic was proposed over two decades ago. While mAbs are 
      particularly suitable candidates for a dual-targeting approach, engineering 
      bispecificity into one molecule can be difficult due to issues with expression 
      and stability, which play a significant role in manufacturability. Here, we 
      address these issues upstream in the process of developing a bispecific antibody 
      (bsAb). Single-chain antibody fragments (scFvs) targeting PDGFRbeta and VEGF-A 
      were selected for superior stability. The scFvs were fused to both termini of 
      human Fc to generate a bispecific, tetravalent molecule. The resulting molecule 
      displays potent activity, binds both targets simultaneously, and is stable in 
      serum. The assembly of a bsAb using stable monomeric units allowed development of 
      an anti-PDGFRB/VEGF-A antibody capable of attenuating angiogenesis through two 
      distinct pathways and represents an efficient method for rapid engineering of 
      dual-targeting molecules.
FAU - Mabry, Robert
AU  - Mabry R
AD  - Antibody Discovery and Assay Technology, ZymoGenetics, Inc., Seattle, WA, USA. 
      mabryr@zgi.com
FAU - Gilbertson, Debra G
AU  - Gilbertson DG
FAU - Frank, Amanda
AU  - Frank A
FAU - Vu, Tuyen
AU  - Vu T
FAU - Ardourel, Dan
AU  - Ardourel D
FAU - Ostrander, Craig
AU  - Ostrander C
FAU - Stevens, Brenda
AU  - Stevens B
FAU - Julien, Susan
AU  - Julien S
FAU - Franke, Secil
AU  - Franke S
FAU - Meengs, Brent
AU  - Meengs B
FAU - Brody, Jennifer
AU  - Brody J
FAU - Presnell, Scott
AU  - Presnell S
FAU - Hamacher, Nels B
AU  - Hamacher NB
FAU - Lantry, Megan
AU  - Lantry M
FAU - Wolf, Anitra
AU  - Wolf A
FAU - Bukowski, Tom
AU  - Bukowski T
FAU - Rosler, Robert
AU  - Rosler R
FAU - Yen, Cindy
AU  - Yen C
FAU - Anderson-Haley, Monica
AU  - Anderson-Haley M
FAU - Brasel, Kenneth
AU  - Brasel K
FAU - Pan, Qi
AU  - Pan Q
FAU - Franklin, Hank
AU  - Franklin H
FAU - Thompson, Penny
AU  - Thompson P
FAU - Dodds, Mike
AU  - Dodds M
FAU - Underwood, Sara
AU  - Underwood S
FAU - Peterson, Scott
AU  - Peterson S
FAU - Sivakumar, Pallavur V
AU  - Sivakumar PV
FAU - Snavely, Mark
AU  - Snavely M
LA  - eng
PT  - Journal Article
DEP - 20100102
PL  - United States
TA  - MAbs
JT  - mAbs
JID - 101479829
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (Antibodies, Bispecific)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Single-Chain Antibodies)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - EC 2.7.10.1 (Receptor, Platelet-Derived Growth Factor beta)
SB  - IM
MH  - Amino Acid Sequence
MH  - Angiogenesis Inhibitors/administration & dosage/*pharmacology
MH  - Animals
MH  - Antibodies, Bispecific/administration & dosage/*pharmacology
MH  - Cell Line, Tumor
MH  - Endothelial Cells/drug effects/pathology
MH  - Female
MH  - Humans
MH  - *Immunotherapy
MH  - Mice
MH  - Mice, SCID
MH  - Molecular Sequence Data
MH  - Neoplasms, Experimental/*drug therapy/immunology
MH  - Neovascularization, Physiologic/drug effects
MH  - Protein Binding
MH  - Protein Engineering
MH  - Protein Stability
MH  - Receptor, Platelet-Derived Growth Factor beta/immunology
MH  - Recombinant Fusion Proteins/genetics/immunology/*metabolism
MH  - Single-Chain Antibodies/genetics/immunology/*metabolism
MH  - Tumor Burden/drug effects
MH  - Vascular Endothelial Growth Factor A/immunology
PMC - PMC2828575
EDAT- 2010/01/13 06:00
MHDA- 2010/06/15 06:00
PMCR- 2011/01/01
CRDT- 2010/01/13 06:00
PHST- 2010/01/13 06:00 [entrez]
PHST- 2010/01/13 06:00 [pubmed]
PHST- 2010/06/15 06:00 [medline]
PHST- 2011/01/01 00:00 [pmc-release]
AID - 10498 [pii]
AID - 1942-0862-2-1-4 [pii]
AID - 10.4161/mabs.2.1.10498 [doi]
PST - ppublish
SO  - MAbs. 2010 Jan-Feb;2(1):20-34. doi: 10.4161/mabs.2.1.10498. Epub 2010 Jan 2.