Demanet C, Brissinck J, De Jonge J, Thielemans K
Physiology Department of the Medical Faculty of Brussels Free University, Belgium.
Blood. 1996 May 15;87(10):4390-8.
The BCL1 lymphoma in Balb/c mice can be successfully treated with bispecific (anti-CD3 x anti-idiotype) antibodies (BSABs). In these experiments, animals were injected intraperitoneally (IP) with 5 x 10(3) tumor cells (day 0) and treated with one single intravenous (IV) injection of 5 micrograms BSAB (day 9). Because cross-linking of the CD3 complex is not in itself sufficient to activate resting T cells, the therapeutic success was mainly based on the progressive retargeting of the relatively small cytotoxic T-lymphocyte effector cell pool already in existence in vivo. For this reason, the therapy lost its effectiveness at higher tumor loads. Two possibilities were explored to treat mice with a higher tumor load (10(5) tumor cells). First multiple injections of BSABs were used, but a dose-related monovalent anti-CD3 immunosuppression was induced. This approach was only beneficial when the immune system was able to recover from the previous injection of BSAB. As a second approach, CD28 costimulation together with BSABs were used in an attempt to activate resting T cells, ultimately enlarging the effector T-cell pool. However, we were repeatedly unsuccessful in attempts to improve our in vivo results using young, naive animals in which the majority of T cells are of the naive phenotype. Only when animals were primed to induce the memory T-cell type was a significantly better outcome observed, and then only with multiple injections of BSABs and anti-CD28 monoclonal antibodies (MoAbs), rather than with BSAB or anti-CD28 MoAb alone. These results suggest that this combination was able to activate memory and effector T cells and to focus them on the tumor, but was unable to activate naive T cells fully. The in vivo potency of the BSAB and CD28 costimulation was shown by the fact that one-tenth of the quantity of BSAB was required to cure animals with 20 times the tumor load.
双特异性（抗CD3×抗独特型）抗体（BSABs）可成功治疗Balb/c小鼠的BCL1淋巴瘤。在这些实验中，于第0天给动物腹腔注射5×10³个肿瘤细胞，并于第9天静脉注射一次5微克的BSAB进行治疗。由于CD3复合物的交联本身不足以激活静息T细胞，治疗成功主要基于对体内已存在的相对少量细胞毒性T淋巴细胞效应细胞库的逐步重定向。因此，在肿瘤负荷较高时该疗法失去效力。探索了两种治疗肿瘤负荷较高（10⁵个肿瘤细胞）小鼠的方法。首先使用多次注射BSABs，但诱导了与剂量相关的单价抗CD3免疫抑制。仅当免疫系统能够从上一次注射BSAB中恢复时，这种方法才有益。作为第二种方法，将CD28共刺激与BSABs一起使用，试图激活静息T细胞，最终扩大效应T细胞库。然而，我们多次尝试使用年轻的、大多数T细胞为幼稚表型的未接触过抗原的动物来改善体内实验结果均未成功。只有当动物被致敏以诱导记忆T细胞类型时，才观察到明显更好的结果，而且只有在多次注射BSABs和抗CD28单克隆抗体（MoAbs）时，而不是单独使用BSAB或抗CD28 MoAb时才会如此。这些结果表明，这种联合能够激活记忆T细胞和效应T细胞并使其聚焦于肿瘤，但无法充分激活幼稚T细胞。BSAB和CD28共刺激的体内效力体现在治愈肿瘤负荷为原来20倍的动物所需的BSAB量仅为原来的十分之一这一事实上。
