A superantigen-antibody fusion protein for T-cell immunotherapy of human B-lineage malignancies

被引:25
作者
Gidlof, C
Dohlsten, M
Lando, P
Kalland, T
Sundstrom, C
Totterman, TH
机构
[1] UNIV UPPSALA HOSP,DEPT CLIN IMMUNOL,S-75185 UPPSALA,SWEDEN
[2] PHARMACIA & UPJOHN INC,RES CTR,LUND,SWEDEN
[3] LUND UNIV,WALLENBERG LAB,DEPT TUMOR IMMUNOL,S-22101 LUND,SWEDEN
[4] UNIV UPPSALA HOSP,DEPT PATHOL,S-75185 UPPSALA,SWEDEN
关键词
D O I
10.1182/blood.V89.6.2089
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The bacterial superantigen staphylococcal enterotoxin A (SEA) is an efficient activator of cytotoxic T cells when presented on major histocompatibility complex (MHC) class II molecules of target cells. Our previous studies showed that such SEA-directed T cells efficiently lysed chronic B-lymphocytic leukemia (B-CLL) cells. Next, we made a mutated SEA-protein A (SEAm-PA) fusion protein with more than 1,000-fold reduced binding affinity for MHC class II compared with native SEA. The fusion protein was successfully used to direct T cells to B-CLL cells coated with different B lineage-directed monoclonal antibodies (MoAbs). In this communication, we constructed a recombinant anti-CD19-Fab-SEAm fusion protein, The MHC class II binding capacity of the SEA part was drastically reduced by a D227A point mutation, whereas the T-cell activation properties were retained. The Fab part of the fusion protein displayed a binding affinity for CD19(+) cells in the nanomolar range, The anti-CD19-Fab-SEAm molecule mediated effective, specific, rapid, and perforin-like T-cell lysis of B-CLL cells at low effector to target cell ratios, Normal CD19(+) B cells were sensitive to lysis, whereas CD34(+) progenitor cells and monocytes/macrophages were resistant. A panel of CD19(+) B-cell lines representing different B-cell developmental stages were efficiently lysed, and the sensitivity correlated with surface ICAM-1 expression. The anti-CD19-Fab-SEAm fusion protein mediated highly effective killing of tumor biopsy cells representing several types of B-cell non-Hodgkin's lymphoma (B-NHL). Humanized severe combined immune deficiency (SCID) mice carrying Daudi lymphoma cells were used as an in vivo therapy model for evaluation of the anti-CD19-Fab-SEAm fusion protein. Greater than 90% reduction in tumor weight was recorded in anti-CD19-Fab-SEAm-treated animals compared with control animals receiving an irrelevant Fab-SEAm fusion protein. The present results indicate that MoAb-targeted superantigens (SASs) may represent a promising approach for T-cell-based therapy of CD19(+) B-cell malignancies. (C) 1997 by The American Society of Hematology.
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页码:2089 / 2097
页数:9
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