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Blood, Vol. 92 No. 6 (September 15), 1998:
pp. 2103-2112
Treatment of B-Cell Lymphoma With Chimeric IgG and Single-Chain Fv
Antibody-Interleukin-2 Fusion Proteins
Shih-Jen Liu,
Yuh-Pyng Sher,
Chou-Chik Ting,
Kuang-Wen Liao,
Cheng-Ping Yu, and
Mi-Hua Tao
From the Graduate Institute of Life Sciences and Department of
Pathology, Tri-Service General Hospital, National Defense Medical
Center, Taipei, Taiwan; the Division of Cancer Research, Institute of
Biomedical Sciences, Academia Sinica, Taipei, Taiwan; the Graduate
Institute of Medical Technology, National Taiwan University, Taipei,
Taiwan; and the Laboratory of Immune Cell Biology, Division of Basic
Science, National Cancer Institute, National Institutes of Health,
Bethesda, MD.
Anti-idiotype (Id) antibodies (Abs) have been shown to be effective
in treatment of B-cell lymphoma in animal models and in clinical
trials. The combination of interleukin-2 (IL-2) can augment the
therapeutic effect of anti-Id Abs. To further improve the power of the
combined therapy, a monoclonal anti-Id Ab, S5A8, specifically
recognizing a murine B-cell lymphoma 38C13, was genetically modified to
contain the IL-2 domain and thus use the unique targeting ability of
Abs to direct IL-2 to the tumor site. Two forms of the anti-Id-IL-2
fusion proteins were constructed: one configuration consisting of
mouse-human chimeric IgG (chS5A8-IL-2) and the other containing only
the variable light (VL) and variable heavy (VH) Ab domains covalently connected by a peptide linker (scFvS5A8-IL-2). Both forms of the anti-Id-IL-2 fusion proteins retained IL-2
biological activities and were equivalent in potentiating tumor cell
lysis in vitro. In contrast, the antigen-binding ability of
scFvS5A8-IL-2 was 30- to 40-fold lower than that of the bivalent
chS5A8-IL-2. Pharmacokinetic analysis showed that scFvS5A8-IL-2 was
eliminated about 20 times faster than chS5A8-IL-2. Finally, it was
shown that chS5A8-IL-2 was very proficient in inhibiting 38C13 tumor growth in vivo, more effectively than a combined therapy with anti-Id
Abs and IL-2, whereas scFvS5A8-IL-2 did not show any therapeutic effect. These results demonstrate that the anti-Id-IL-2 fusion protein
represents a potent reagent for treatment for B-cell lymphoma and that
the intact IgG fusion protein is far more effective than its
single-chain counterpart.
© 1998 by The American Society of Hematology.
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