Treatment of B-cell lymphoma with chimeric IgG and single-chain Fv antibody-interleukin-2 fusion proteins.
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.
Liu
S J
SJ
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.
Sher
Y P
YP
Ting
C C
CC
Liao
K W
KW
Yu
C P
CP
Tao
M H
MH
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D001666:Binding Sites, Antibody; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000235:genetics / Q000627:therapeutic use*; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000235:genetics / Q000627:therapeutic use*; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D000888:Antibodies, Anti-Idiotypic; D000970:Antineoplastic Agents; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D007135:Immunoglobulin Variable Region; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins