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J. Biol. Chem., Vol. 280, Issue 50, 41546-41552, December 16, 2005

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Structural Basis of Antigen Mimicry in a Clinically Relevant Melanoma Antigen System^*

Chien-Chung Chang1, Francisco G. Hernandez-Guzman, Wei Luo, Xinhui Wang, Soldano Ferrone2, and Debashis Ghosh¶3

From the Department of Immunology and of ^¶Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263 and the Hauptman-Woodward Medical Research Institute, Inc., Buffalo, New York 14203

Although mimics of human tumor antigens are effective immunogens to overcome host unresponsiveness to the nominal antigen, the structural basis of this mimicry remains poorly defined. Therefore, in this study we have characterized the structural basis of the human high molecular weight-melanoma-associated antigen (HMW-MAA) mimicry by the mouse anti-idiotypic (anti-id) monoclonal antibody (mAb) MK2-23. Using x-ray crystallography, we have characterized the three-dimensional structure of the anti-id mAb MK2-23 Fab' and shown that its heavy chain complementarity-determining region (CDR3) (H3) and its light chain CDR1 (L1) are closely associated. These moieties are the source of HMW-MAA mimicry, since they display partial amino acid sequence homology along with a similar structural fold with the HMW-MAA core protein. Furthermore, a 15-residue peptide comprising the H3 loop of anti-id mAb MK2-23 demonstrates HMW-MAA-like in vitro and in vivo reactivity. This peptide in conjunction with the structural data will facilitate the characterization of the effect of the degree of antigen mimicry on the induction of a self-antigen-specific immune response by a mimic.

Received for publication, July 12, 2005 , and in revised form, October 3, 2005.

The atomic coordinates and structure factors (code 2AAB) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) DQ241816 [GenBank] and DQ241817 [GenBank] .

^* This work was supported in part by United States Public Health Service Grants P01 CA89480 and R01 CA105500 awarded by the NCI/National Institutes of Health, DHHS, and by a grant from the Harry J. Lloyd Charitable Trust. 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 Supported in part by a Susan G. Komen Breast Cancer Foundation predoctoral fellowship.

² To whom correspondence may be addressed: Dept. of Immunology, Roswell Park Cancer Inst., Elm and Carlton Sts., Buffalo, NY 14263. Tel.: 716-845-8534; Fax: 716-8457613; E-mail: soldano.ferrone{at}roswellpark.org.

³ To whom correspondence may be addressed: Hauptman-Woodward Medical Research Inst., Inc., 700 Ellicott St., Buffalo, NY 14203. Tel.: 716-898-8617; Fax: 716-898-8660; E-mail: ghosh{at}hwi.buffalo.edu.

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