Protein engineering for targeted delivery of radionuclides to tumors

Traditional cancer treatment strategies include systemic chemotherapy, external beam radiation, and surgical excision. Chemotherapy is nonspecific, and targets all rapidly dividing cells. External beam radiation and surgery only target known cancer sites. However, targeted therapeutics, such as antibodies, will bind to all cancer cells that express the targeted antigen, including small metastases that are invisible by current imaging technology. In the past decade, nine antibodies have been approved for the treatment of cancer and are demonstrating moderate success in the clinic. Some of these antibodies have intrinsic toxic effects and block the interaction of growth factors or induce cell death. Other antibodies are conjugated to drugs, toxins, or radioactive isotopes. Unfortunately, antibodies exhibit slow clearance from the body and exposure of healthy tissues to toxins or radiation can result in undesirable side effects that limit the doses that can be safety administered to the patient. We have used rational engineering design and mathematical modeling to develop a novel pretargeted radioimmunotherapy (PRIT) approach for the treatment of cancer. In PRIT, a bifunctional antibody is administered and allowed to bind to a cancer antigen. After sufficient tumor uptake of the antibody, a small molecule carrying a radionuclide is administered and captured by the pretargeted antibody while unbound molecules clear rapidly from the body. PRIT combines the high binding specificity of antibodies with the rapid clearance properties of small molecules. We have identified a small molecule metal chelate, DOTA, which exhibits rapid whole-body clearance and that has demonstrated safety in humans.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Chemical Engineering.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2010

Author dc:creator

• Orcutt, Kelly Davis

Advisor dc:contributor.advisor

• K Dane Wittrup.

• Chemical Engineering.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/58268

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/58268