Macrocyclic Radiochelates for Antibody Imaging and Therapy of Breast Cancer.
Abstract
Conjugation of bifunctional chelating agents allows monoclonal antibodies (mAbs) to be labeled with radiometals for delivery of diagnostic or therapeutic radiation to primary breast tumors or metastatic disease. Physiologically stable radiometal chelates, such as those of 1,4,7,10- tetraazacyclododecane N,N',N",N"'-tetraacetic acid (DOTA), are desirable to reduce dose-limiting radiation toxicity to normal tissues. Two new classes of DOTA derivatives, maleimidocysteineamido-DOTA derivatives and hydrazido-DOTA derivatives, were synthesized and conjugated, respectively, to reduced interchain disulfide bonds and oxidized carbohydrate residues of the anti-carcinoembryonic antigen mAbs cT84.66 and ZCE025. Conjugates of cT84.66 prepared with maleimide derivatives of DOTA exhibited near-quantitative labeling with the imaging radiometal. In and the therapy radiometal 90Y, quantitative immunoreactivity, and linker-specific cleavage reactions which were considerably faster at pH 7.4 than at pH 5.4. Biodistribution studies demonstrated that this property imparted favorable tumor uptake and normal tissue clearance to radiolabeled cT84.66. Conjugation of oxidized cT84.66 with hydrazido-DOTA resulted in extensive antibody aggregation and low radiometal labeling yields. Conjugation of oxidized ZCE025 with hydrazido-DOTA, carbohydrazido-DOTA, and hydrazidocysteineamido-DOTA was also unsuccessful. It is possible that modification of the ZCE025 conjugation procedure or use of a CT84.66 construct with a genetically engineered oligosaccharide will allow successful attachment and radiometal labeling of the hydrazido-DOTA derivatives.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 1998
- Accession Number
- ADA349597
Entities
People
- Michael R. Lewis