期刊
PROTEIN ENGINEERING DESIGN & SELECTION
卷 26, 期 3, 页码 187-193出版社
OXFORD UNIV PRESS
DOI: 10.1093/protein/gzs096
关键词
anti-carcinoembryonic antigen; bispecific antibody; pre-targeted radioimmunotherapy
资金
- National Cancer Institute at the National Institute of Health [P01 CA43904]
- Norwegian Research Council [179573/V40]
- South-Eastern Norway Regional Health Authority [39375]
A series of anti-tumor/anti-chelate bispecific antibody formats were developed for pre-targeted radioimmunotherapy. Based on the anti-carcinoembryonic antigen humanized hT84.66-M5A monoclonal antibody and the anti-DOTA C8.2.5 scFv antibody fragment, this cognate series of bispecific antibodies were radioiodinated to determine their tumor targeting, biodistribution and pharmacokinetic properties in a mouse xenograft tumor model. The in vivo biodistribution studies showed that all the bispecific antibodies exhibited specific high tumor uptake but the tumor targeting was approximately one-half of the parental anti-CEA mAb due to faster blood clearance. Serum stability and FcRn studies showed no apparent reason for the faster blood clearance. A dual radiolabel biodistribution study revealed that the In-111-DOTA bispecific antibody had increased liver and spleen uptake, not seen for the I-125-version due to metabolism and release of the radioiodine from the cells. These data suggest increased clearance of the antibody fusion formats by the mononuclear phagocyte system. Importantly, a pre-targeted study showed specific tumor uptake of Lu-177-DOTA and a tumor : blood ratio of 199 : 1. This pre-targeted radiotherapeutic and substantial reduction in the radioactive exposure to the bone marrow should enhance the therapeutic potential of RIT.
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