A dual-targeting PDGFRbeta/VEGF-A molecule assembled from stable antibody fragments demonstrates anti-angiogenic activity in vitro and in vivo

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 i...

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Bibliographic Details
Published in:mAbs 2010-01, Vol.2 (1), p.20-34
Main Authors: Mabry, Robert, Gilbertson, Debra G, Frank, Amanda, Vu, Tuyen, Ardourel, Dan, Ostrander, Craig, Stevens, Brenda, Julien, Susan, Franke, Secil, Meengs, Brent, Brody, Jennifer, Presnell, Scott, Hamacher, Nels B, Lantry, Megan, Wolf, Anitra, Bukowski, Tom, Rosler, Robert, Yen, Cindy, Anderson-Haley, Monica, Brasel, Kenneth, Pan, Qi, Franklin, Hank, Thompson, Penny, Dodds, Mike, Underwood, Sara, Peterson, Scott, Sivakumar, Pallavur V, Snavely, Mark
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Angiogenesis Inhibitors - administration & dosage
Angiogenesis Inhibitors - pharmacology
Animals
Antibodies, Bispecific - administration & dosage
Antibodies, Bispecific - pharmacology
Cell Line, Tumor
Endothelial Cells - drug effects
Endothelial Cells - pathology
Female
Humans
Immunotherapy
Mice
Mice, SCID
Molecular Sequence Data
Neoplasms, Experimental - drug therapy
Neoplasms, Experimental - immunology
Neovascularization, Physiologic - drug effects
Protein Binding
Protein Engineering
Protein Stability
Receptor, Platelet-Derived Growth Factor beta - immunology
Recombinant Fusion Proteins - genetics
Recombinant Fusion Proteins - immunology
Recombinant Fusion Proteins - metabolism
Single-Chain Antibodies - genetics
Single-Chain Antibodies - immunology
Single-Chain Antibodies - metabolism
Tumor Burden - drug effects
Vascular Endothelial Growth Factor A - immunology
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Summary: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.
ISSN:1942-0870