Demanet C, Brissinck J, Leo O, Moser M, Thielemans K
Laboratory of Physiology, Medical School of the Vrije Universiteit Brussel (VUB), Belgium.
Cancer Res. 1994 Jun 1;54(11):2973-8.
We reported previously on the successful use of bispecific antibodies in two well characterized B-cell lymphoma models. These bispecific antibodies were hybrid-hybridoma antibodies with dual specificity for the TcR/CD3 complex and for the tumor-specific idiotype of the surface IgM expressed by the lymphoma cells. Class-matched control antibodies, either monovalent for CD3, monovalent for idiotype, or bivalent for these surface markers, were always used in parallel with the bispecific antibodies. We extended our studies to determine the relative contribution of antibody-dependent cellular cytotoxicity and a T-cell-mediated therapeutic effect in the BCL1 lymphoma model. In tumor-bearing mice depleted of CD4+, CD8+ or both T-cell subsets and treated with bispecific antibodies, we could show that both T-cell populations contribute to the therapeutic outcome and have an additive role. In vitro studies demonstrate that bridging BCL1 tumor cells to T-cells by bispecific antibodies induces T-cell activation and secretion of tumor growth inhibiting lymphokines by both CD4+ and CD8+ T-cell populations. Particularly gamma-interferon seems to be the major tumor-inhibiting substance for BCL1 tumor cells. However, in vivo experiments using anti-cytokine antibodies showed that both gamma-interferon and tumor necrosis factor alpha have an effect on the tumor growth. The former acts directly by inhibiting tumor growth, the latter via an indirect mechanism, possibly by activating macrophages. In conclusion, our results show that induction of targeted cytolytic activity by the direct CD3/TcR cross-linking and development of targeted cytotoxic activity, mediated by gamma-interferon, by both T-cell subsets, contribute to the therapeutic success of bispecific antibody therapy.
我们之前报道了双特异性抗体在两种特征明确的B细胞淋巴瘤模型中的成功应用。这些双特异性抗体是杂交-杂交瘤抗体，对TcR/CD3复合物以及淋巴瘤细胞表面IgM表达的肿瘤特异性独特型具有双重特异性。与双特异性抗体同时使用的总是类匹配的对照抗体，它们对CD3为单价、对独特型为单价或对这些表面标志物为双价。我们扩展了研究，以确定在BCL1淋巴瘤模型中抗体依赖性细胞毒性和T细胞介导的治疗效果的相对贡献。在去除了CD4+、CD8+或这两个T细胞亚群的荷瘤小鼠中并用双特异性抗体进行治疗后，我们可以表明这两个T细胞群体均对治疗结果有贡献且具有相加作用。体外研究表明，双特异性抗体将BCL1肿瘤细胞与T细胞连接可诱导T细胞活化以及CD4+和CD8+ T细胞群体分泌抑制肿瘤生长的淋巴因子。特别是γ干扰素似乎是BCL1肿瘤细胞的主要肿瘤抑制物质。然而，使用抗细胞因子抗体的体内实验表明，γ干扰素和肿瘤坏死因子α均对肿瘤生长有影响。前者通过抑制肿瘤生长直接起作用，后者通过间接机制起作用，可能是通过激活巨噬细胞。总之，我们的结果表明，直接的CD3/TcR交联诱导靶向溶细胞活性以及两个T细胞亚群介导的由γ干扰素介导的靶向细胞毒性活性的发展，有助于双特异性抗体治疗的成功。
