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.