This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Monoclonal antibodies (mAbs) as therapeutic agents are recognized for their specificity, and ability to elicit an immune response, antagonize signaling pathways, and as vehicles to deliver cytotoxic compounds at the disease site. Many of the mAbs in the clinic typically recognize the overexpression of human-derived antigens on the surface of diseased cells, the most prominent being cetuximab (Erbitux) and trastuzumab (Herceptin) which target the Erb family (e.g., EGFR and Her2). These receptors are frequently overexpressed in solid tumors including metastatic colorectal, head and neck and breast cancers, but are also normally expressed in epithelial cells. At therapeutic doses, the receptors in normal tissues are also engaged, leading to side effects (e.g., cardiotoxicity and PML). These side effects reduce the efficacy, narrow the therapeutic window, and limit the length of the administration of mAb treatment. To address these serious complications, we have recently developed a method to modulate the antigen affinity of therapeutic mAbs and use a tumor-associated protease to active the mAb at the disease site. We show that cleavage of the 'pro-antibody'restores the mAb antigen affinity. We are now interested in coupling small molecules to fine tune the modulation of antibody affinity. To do so, we will use a brominated, small molecule library to soak crystals of the therapeutic Fab fragment, and use synchrotron radiation to identify bound fragments through SAD/MAD phasing. This information will allow us to couple these small molecules to peptides and generate novel masking agents.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR001209-32
Application #
8362351
Study Section
Special Emphasis Panel (ZRG1-BCMB-P (40))
Project Start
2011-03-01
Project End
2012-02-29
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
32
Fiscal Year
2011
Total Cost
$1,368
Indirect Cost
Name
Stanford University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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