Protease-Activated Antibodies for Diagnostics and Therapy

Tuesday, October 18, 2011: 9:10 AM
M100 H (Minneapolis Convention Center)
Patrick S. Daugherty and Tobias Schoep, Chemical Engineering, University of California, Santa Barbara, Santa Barbara, CA

Antibody therapeutics represent the single largest class of biological therapeutics, but increasingly exhibit toxicities due to target inhibition in healthy tissues. Such toxicities have resulted in costly failures in all stages of preclinical and clinical development. Furthermore, the toxicities of approved antibody therapeutics reduce patient safety and compliance with therapy. Given these problems, we devised a general strategy to construct antibodies whose in vivo activity is regulated by proteolytic enzymes that are locally activated at sites of pathology.  In an effort to restrict antibody activity to unstable atherosclerotic plaques that increase the risk of heart attack and stroke, protease-activated antibodies (pro-antibodies) targeting VCAM-1 were constructed by tethering an engineered prodomain to the antibody.  Prodomains consisting of a peptide ligand that blocks the antibody binding site and a flexible linker containing a protease substrate strongly attenuated antibody binding activity. However, antibody activity was fully restored upon exposure to proteases known to be locally activated in plaques. The VCAM-1 pro-antibody selectively localized to pathological aortic plaques in an ApoE KO mouse model of atherosclerosis. Importantly, the pro-antibody spared healthy tissues that were targeted by a conventional VCAM-1 antibody.  Pro-antibodies thus represent a new strategy to control the distribution of antibody activity in vivo, and may be useful for reducing therapeutic antibody toxicities or for drugging challenging targets with broad tissue distribution.

Extended Abstract: File Not Uploaded
See more of this Session: Protein Engineering I - Therapeutics
See more of this Group/Topical: Food, Pharmaceutical & Bioengineering Division