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Conjugates of antibodies and metal chelates in cancer therapy
METALS IN MEDICINE
C04
187
CONJUGATES OF ANTIBODIES AND METAL CHELATES IN CANCER THERAPY
Min Li,a C l a u d e F. Meares, a Oliver R e n n , a Q a n s y S a l a k o , b D a v i d L. K u k i s , b Laird Miers,b S a l l y J. DeNardo,b a n d G i o v a n n i Paganellie aDept, of Chemistry, University of California, Davis, CA 95616 bDept, of lnternal Medicine, University of California Davis Medical Center, Sacramento, CA 95817 cSvc. of Nuclear Medicine, Istituto Europeo di Oncologia, Via Ripamonti 435 20141, Milan, ITALY Metallic radioisotopes s u c h as I 1l ln ' 90y, a n d 67Cu are p r i m a r y candidates for labeling monoclonal antibodies due to their favorable physical properties for imaging a n d therapy. The h u m a n / m o u s e chimeric antibody L6 recognizes a cell surface antigen highly expressed on lung, breast, colon, a n d ovarian carcinomas. We are working to extend the u s e of this antibody to include other radionuclides. Yttrium-90 a n d indium-111 have been a t t a c h e d to chimeric monoclonal antibody L6 with a macrocyclic bifunctional chelating agent (DOTA-peptide isothiocyanate). The bifunctional chelating agent was pre-labeled with either radiometal a n d t h e n conjugated to the antibody [1]. Studies in h u m a n patients showed excellent indium- 111 SPECT images of b r e a s t cancer lesions 24 h after injection. Radiolabeled monoclonal antibodies are widely u s e d in the detection and t r e a t m e n t of cancer, b u t several problems still prevent full clinical exploitation of these reagents. Low t u m o r / b a c k g r o u n d ratios in i m m u n o - s c i n t i g r a p h y a n d high b a c k g r o u n d radioactivity in t h e r a p y can be limiting factors. The strategy of pre-targeting, e.g., with the avidin-biotin system, m a y overcome these limitations. The use of biotinylated a n t i t u m o r antibodies, followed b y avidin a n d t h e n b y a biotin-chelate conjugate in a three step procedure to image cancer sites h a s been d e m o n s t r a t e d [2]. 1. M. Li, C.F. Meares, G-R. Zhong, L. Miers, C-Y. Xiong, a n d S.J. DeNardo. Bioconjugate Chemistry, 5, 101 (1994). 2. G. PaganeUi, Cancer Research, 51, 5960 (1991).
C04
187
CONJUGATES OF ANTIBODIES AND METAL CHELATES IN CANCER THERAPY
Min Li,a C l a u d e F. Meares, a Oliver R e n n , a Q a n s y S a l a k o , b D a v i d L. K u k i s , b Laird Miers,b S a l l y J. DeNardo,b a n d G i o v a n n i Paganellie aDept, of Chemistry, University of California, Davis, CA 95616 bDept, of lnternal Medicine, University of California Davis Medical Center, Sacramento, CA 95817 cSvc. of Nuclear Medicine, Istituto Europeo di Oncologia, Via Ripamonti 435 20141, Milan, ITALY Metallic radioisotopes s u c h as I 1l ln ' 90y, a n d 67Cu are p r i m a r y candidates for labeling monoclonal antibodies due to their favorable physical properties for imaging a n d therapy. The h u m a n / m o u s e chimeric antibody L6 recognizes a cell surface antigen highly expressed on lung, breast, colon, a n d ovarian carcinomas. We are working to extend the u s e of this antibody to include other radionuclides. Yttrium-90 a n d indium-111 have been a t t a c h e d to chimeric monoclonal antibody L6 with a macrocyclic bifunctional chelating agent (DOTA-peptide isothiocyanate). The bifunctional chelating agent was pre-labeled with either radiometal a n d t h e n conjugated to the antibody [1]. Studies in h u m a n patients showed excellent indium- 111 SPECT images of b r e a s t cancer lesions 24 h after injection. Radiolabeled monoclonal antibodies are widely u s e d in the detection and t r e a t m e n t of cancer, b u t several problems still prevent full clinical exploitation of these reagents. Low t u m o r / b a c k g r o u n d ratios in i m m u n o - s c i n t i g r a p h y a n d high b a c k g r o u n d radioactivity in t h e r a p y can be limiting factors. The strategy of pre-targeting, e.g., with the avidin-biotin system, m a y overcome these limitations. The use of biotinylated a n t i t u m o r antibodies, followed b y avidin a n d t h e n b y a biotin-chelate conjugate in a three step procedure to image cancer sites h a s been d e m o n s t r a t e d [2]. 1. M. Li, C.F. Meares, G-R. Zhong, L. Miers, C-Y. Xiong, a n d S.J. DeNardo. Bioconjugate Chemistry, 5, 101 (1994). 2. G. PaganeUi, Cancer Research, 51, 5960 (1991).