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Sulfhydryl-Based Tumor Antigen-Carrier Protein Conjugates Stimulate Superior Antitumor Immunity against B Cell Lymphomas¹

Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095

Therapeutic vaccination of B cell lymphoma patients with tumor-specific Ig (idiotype, or Id) chemically coupled to the immunogenic foreign carrier protein keyhole limpet hemocyanin (KLH) using glutaraldehyde has shown promising results in early clinical trials, and phase III trials are underway. However, glutaraldehyde Id-KLH vaccines fail to elicit anti-Id immune and clinical responses in many patients, possibly because glutaraldehyde reacts with lysine, cysteine, tyrosine, and histidine residues, damaging critical immunogenic epitopes. A sulfhydryl-based tumor Ag-carrier protein conjugation system using maleimide chemistry was used to enhance the efficacy of Id-KLH vaccines. Maleimide Id-KLH conjugates eradicated A20 lymphoma from most tumor-bearing mice, whereas glutaraldehyde Id-KLH had little efficacy. Maleimide Id-KLH elicited tumor-specific IgG Abs and T cells, with CD8⁺ T cells being the major effectors of antilymphoma immunity. Maleimide Id-KLH vaccines also demonstrated superior efficacy in 38C13 and BCL-1 lymphoma models, where Abs were shown to be critical for protection. Importantly, standard glutaraldehyde Id-KLH conjugation procedures could result in "overconjugation" of the tumor Ag, leading to decreased efficacy, whereas the heterobifunctional maleimide-based conjugation yielded potent vaccine product regardless of conjugation duration. Under lysosomal processing conditions, the Id-carrier protein linkage was cleavable only after maleimide conjugation. Maleimide KLH conjugation was easily performed with human Igs analogous to those used in Id-KLH clinical trials. These data support the evaluation of sulfhydryl-based Id-KLH vaccines in lymphoma clinical trials and possibly the use of tumor Ag-carrier protein vaccines for other cancers.

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 funded by the Albert Yu and Mary Bechmann Foundation, which we thank. J.M.T. is the recipient of a Clinical Investigator Award from the Damon Runyon Cancer Research Foundation (CI-26-05).

² Address correspondence and reprint requests to Dr. John M. Timmerman, Division of Hematology and Oncology, Center for Health Sciences, Room 42-121, 10833 LeConte Avenue, University of California, Los Angeles Medical Center, Los Angeles, CA, 90095-1678. E-mail address: jtimmerman{at}mednet.ucla.edu

³ Abbreviations used in this paper: KLH, keyhole limpet hemocyanin; SMCC, succinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate; sulfo-SMCC, sulfosuccinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate.