CD3 x CD28 cross-interacting bispecific antibodies improve tumor cell dependent T-cell activation

被引:9
|
作者
Willems, A
Schoonooghe, S
Eeckhout, D
De Jaeger, G
Grooten, J
Mertens, N
机构
[1] State Univ Ghent VIB, Dept Mol Biomed Res, B-9052 Ghent, Belgium
[2] State Univ Ghent VIB, Dept Plant Syst Biol, B-9052 Ghent, Belgium
关键词
T lymphocytes; co-stimulation; bispecific antibodies; tumor immunotherapy; recombinant antibodies; CD28;
D O I
10.1007/s00262-005-0671-8
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Bispecific antibodies (Bs-Abs) containing an anti-CD3 and an anti-TAA specificity can recruit T cells to the tumor for cancer immunotherapy. To be effective, efficient activation at the tumor site is a prerequisite. This can be achieved by triggering both the T-cell receptor and the co-stimulatory molecule CD28. We engineered two recombinant cross-interacting Bs-Abs (CriBs-Abs) by incorporating a peptide tag and its cognate single-chain variable fragment (scFv), respectively, into a pair of (tumor x CD3) and (tumor x CD28) binding Bs-Abs. A 30-fold lower concentration of the activating CriBs-Ab as compared to non interacting Bs-Ab was sufficient for strong T-cell activation in the presence of tumor cells. One thousand-fold higher concentrations of both CriBs-Abs were required for marginal T-cell activation (70-fold below maximal response) in the absence of tumor cells. An optimized stoichiometry (1 : 1000) of activating versus co-stimulating CriBs-Ab thus allowed low doses of activating CriBs-Ab to induce tumor-cell dependent T-cell activation when used in combination with high concentrations of the pre-targeted co-stimulating CriBs-Ab in vitro. This indicates a large window of operation in which only tumor cell dependent T-cell activation is induced and systemic tumor cell independent T-cell activation is avoided, while ensuring optimal activation with a low concentration of the activating CriBs-Ab, which has the highest potential to induce toxic effects in vivo.
引用
收藏
页码:1059 / 1071
页数:13
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