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* Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111; and
Department of Anesthesia, University of California, San Francisco, CA 94110
Unconjugated mAbs have emerged as useful cancer therapeutics. Ab-dependent cellular cytotoxicity (ADCC) is believed to be a major antitumor mechanism of some anticancer Abs. However, the factors that regulate the magnitude of ADCC are incompletely understood. In this study, we described the relationship between Ab affinity and ADCC. A series of human IgG1 isotype Abs was created from the anti-HER2/neu (also named c-erbB2) C6.5 single-chain Fv (scFv) and its affinity mutants. The scFv affinities range from 10–7 to 10–11 M, and the IgG Abs retain the affinities of the scFv from which they were derived. The apparent affinity of the Abs ranged from nearly 10–10 M (the lowest affinity variant) to almost 10–11 M (the other variants). The IgG molecules were tested for their ability to elicit ADCC in vitro against three tumor cell lines with differing levels of HER2/neu expression using unactivated human PBMC from healthy donors as the effector cells. The results demonstrated that both the apparent affinity and intrinsic affinity of the Abs studied regulate ADCC. High-affinity tumor Ag binding by the IgGs led to the most efficient and powerful ADCC. Tumor cells expressing high levels of HER2/neu are more susceptible to the ADCC triggered by Abs than the cells expressing lower amounts of HER2/neu. These findings justify the examination of high affinity Abs for ADCC promotion. Because high affinity may impair in vivo tumor targeting, a careful examination of Ab structure to function relationships is required to develop optimized therapeutic unconjugated Abs.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants CA50633 and CA121033 (to L.M.W.), and Grant CA06927 all from the National Cancer Institute, the Bernard and Rebecca S. Bernard Foundation, the Frank Strick Foundation, and by an appropriation from the Commonwealth of Pennsylvania.
2 Y.T. and J.L. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Louis M. Weiner, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111. E-mail address: Louis.Weiner{at}fccc.edu
4 Abbreviations used in this paper: ADCC, Ab-dependent cellular cytotoxicity; CDC, complement-dependent cytotoxicity; MFI, mean fluorescence intensity; scFv, single-chain Fv; ECD, extracellular domain; CHO, Chinese hamster ovary.
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