HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Sulfhydryl-based tumor antigen-carrier protein conjugates stimulate superior antitumor immunity against B cell lymphomas.

Abstract
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.
AuthorsDavid J Betting, Kamran Kafi, Alireza Abdollahi-Fard, Sara A Hurvitz, John M Timmerman
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 181 Issue 6 Pg. 4131-40 (Sep 15 2008) ISSN: 1550-6606 [Electronic] United States
PMID18768870 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antigens, Neoplasm
  • Cancer Vaccines
  • Carrier Proteins
  • Cross-Linking Reagents
  • Immunoglobulin Idiotypes
  • Maleimides
  • Vaccines, Conjugate
  • maleimide
  • Glutaral
Topics
  • Animals
  • Antigens, Neoplasm (administration & dosage, immunology)
  • CD4-Positive T-Lymphocytes (immunology)
  • Cancer Vaccines (administration & dosage, immunology)
  • Carrier Proteins (administration & dosage, immunology)
  • Cell Line, Tumor
  • Cross-Linking Reagents (metabolism)
  • Glutaral (metabolism)
  • Humans
  • Immunization, Passive
  • Immunoglobulin Idiotypes (administration & dosage, immunology, metabolism)
  • Lymphoma, B-Cell (immunology, prevention & control)
  • Maleimides (administration & dosage, immunology)
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Neoplasm Transplantation
  • Vaccines, Conjugate (administration & dosage, immunology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: