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Idiotypic vaccination against human B-cell lymphoma. Rescue of variable
region gene sequences from biopsy material for assembly as single-chain Fv
personal vaccines
RE Hawkins, D Zhu, M Ovecka, G Winter, TJ Hamblin, A Long and FK Stevenson
Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
Idiotypic determinants on neoplastic B cells could provide tumor antigens
for vaccination of patients with B-cell tumors. Because this approach
requires an individual vaccine for each patient, simple methods for
obtaining idiotypic antigen are desirable. Using polymerase chain reaction
(PCR) with family-based V-gene and J-region primers, the variable region
genes of heavy and light chains (VH and VL) of Ig have been obtained from
biopsy material from 13 patients with B-cell tumors. In each case, analysis
of random clones derived from the PCR product showed repeated,
clonally-related sequences, whereas normal lymphoid tissue generated no
repeated sequences. In 3/3 cases, the repeated sequences were found to be
the same as those in a tumor-derived hybridoma. Mutational patterns in the
V-genes differed among the tumors, with follicular lymphoma tending to be
more highly mutated. The individual VH and VL sequences have been assembled
with a flexible linker sequence to encode single-chain Fv (scFv). The scFv
sequences can be cloned into bacterial expression vectors to produce
protein, or into vectors suitable for direct vaccination using naked DNA.
In a model system, expressed scFv protein retained all idiotypic
determinants defined by a panel of five anti-idiotypic monoclonal
antibodies (MoAbs). Similarly, expressed scFv proteins from two patients
were shown to react with anti-idiotypic antibodies. This approach allows
production of potential vaccines from surgical biopsies within 2 to 3
weeks.
Volume 83,
Issue 11,
pp. 3279-3288,
06/01/1994
Copyright © 1994 by The American Society of Hematology
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