Serum half-life and tumor localization of a chimeric antibody deleted of the CH2 domain and directed against the disialoganglioside GD2.
Open Access
- 1 August 1990
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 87 (15), 5702-5705
- https://doi.org/10.1073/pnas.87.15.5702
Abstract
Recombinant techniques allow one to engineer an antibody molecule and, in this way, manipulate its properties and functions. We engineered a chimeric human/mouse antibody to the tumor-associated antigen ganglioside GD2, with the aim of decreasing its serum half-life, maintaining its full antigen-binding capacity, and deleting its effector functions, thus making it a potentially useful reagent for the radioimaging of tumors. To this end, the constant region of the human .gamma.1 chain was mutated by deleting the second domain (CH2). Here we show that the CH2-deleted antibody (ch14.18-.DELTA.CH2) was cleared from the blood of athymic (nu/nu) mice bearing human melanoma tumors with the same kinetics as human IgG F(ab'')2. At a .beta. t1/2 of 12 hr, 0.9% of the injected dose of 125I-labeled ch14.18-.DELTA.CH2 was found per milliliter of blood 24 hr after i.v. injection. In biodistribution experiments, 125I-labeled ch14.18-.DELTA.CH2 targeted specifically to melanoma xenografts, achieving optimal tumor-to-tissue ratios 12-16 hr after i.v. injection. ch14-18-.DELTA.CH2 was localized to the melanoma tumors more rapidly and with better localization ratios than the intact chimeric antibody ch14.18. Sixteen hours after i.v. injection, the tumor-to-blood and tumor-to-liver ratios of ch14.18-.DELTA.CH2 were 5 and 12, respectively, while optimal localization ratios obtained for ch14.18 were 1 and 5, respectively, but 96 hr after injection. A reagent such as ch14.18-.DELTA.CH2 should be useful for radioimmunodetection of human tumors because of reduced immunogenicity, increased targeting specificity, and rapid clearance from circulation.Keywords
This publication has 27 references indexed in Scilit:
- High-level expression of chimeric antibodies using adapted cDNA variable region cassettesJournal of Immunological Methods, 1989
- Labeling monoclonal antibodies and F(ab')2 fragments with the alpha-particle-emitting nuclide astatine-211: preservation of immunoreactivity and in vivo localizing capacity.Proceedings of the National Academy of Sciences, 1989
- Mouse/human chimeric monoclonal antibody in man: kinetics and immune response.Proceedings of the National Academy of Sciences, 1989
- Improved procedure for preparation of F(ab′)2 fragments of mouse IgGs by papain digestionJournal of Immunological Methods, 1989
- Specific and stable labeling of antibodies with technetium-99m with a diamide dithiolate chelating agent.Proceedings of the National Academy of Sciences, 1988
- Generation of an antibody with enhanced affinity and specificity for its antigen by protein engineeringNature, 1987
- Current status of cancer imaging with radiolabeled antibodiesZeitschrift für Krebsforschung und Klinische Onkologie, 1987
- Comparative tumour localization of antibody fragments and intact IgG in nude mice bearing a CEA-producing human colon tumour xenograftEuropean Journal of Cancer and Clinical Oncology, 1985
- Transfectomas Provide Novel Chimeric AntibodiesScience, 1985
- Preparation of F(ab′)2 fragments from mouse IgG of various subclassesJournal of Immunological Methods, 1983