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The Development of Bispecific Hexavalent Antibodies as a Novel Class of DOCK-AND-LOCKTM (DNLTM) Complexes

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Author(s): Chien-Hsing Chang | Edmund A. Rossi | Yang Wang | Thomas M. Cardillo | David M. Goldenberg

Journal: Antibodies
ISSN 2073-4468

Volume: 2;
Issue: 2;
Start page: 353;
Date: 2013;
Original page

Keywords: DNLTM | bispecific | hexavalent | conjugation | site-specific | antibodies | cancer

ABSTRACT
The DOCK-AND-LOCKTM (DNLTM) method provides a modular approach to develop multivalent, multifunctional complexes of defined structures, of which bispecific hexavalent antibodies (bsHexAbs) are prominent examples with potential applications in targeted therapy for malignant, autoimmune, and infectious diseases. Currently, bsHexAbs are constructed by derivatizing a divalent IgG, at the carboxyl termini of either the heavy chain (the CH3-format) or the light chain (the Ck-format), to contain two stabilized dimers of Fab having a different specificity from the IgG. In this review, we briefly outline the features of the DNLTM method and describe key aspects of bsHexAbs examined with diverse preclinical studies, which include binding affinity to target cells, induction of signaling pathways, effector functions, serum stability, pharmacokinetics, and antitumor activity in human tumor xenograft models. Our findings favor the selection of the CK- over the CH3-format for further exploration of bsHexAbs in clinical trials.
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