Lindhofer H, Menzel H, Günther W, Hültner L, Thierfelder S
Forschungszentrum für Umwelt und Gesundheit (GSF)-Institut für Immunologie, Munich, Germany.
Blood. 1996 Dec 15;88(12):4651-8.
Despite improved procedures in chemotherapy and bone marrow transplantation (BMT), post-BMT leukemia relapse rates have remained rather constant in the last decade. Immunotherapy with monoclonal or bispecific antibodies (bsAb) is a promising approach to improve this situation, but is hampered by the absence of tumor-specific antigens on the majority of tumors. To evade this problem, we developed a new tumor-specific approach in which bispecific antibodies exploit chimerism after allogeneic BMT by redirecting donor T cells against recipient-specific antigens on tumor cells. Two different leukemia relapse models were established using a T-cell lymphoma (ST-1) and a B-cell lymphoma (BCL1) to evaluate the efficiency of such a therapy. In these experiments, irradiated BALB/c (Thy-1.2+, I-Ad) mice were transplanted with C57BL/6 Thy-1.1 (I-Ab) BM cells under the protection of graft-versus-host disease-preventing monoclonal antibodies. Forty-five days after BMT, the chimeric mice were injected with either 2 x 10(4) recipient-type, Thy-1.2+, CD3- ST-1 cells or major histocompatability complex (MHC) class II+ (I-Ad)-BCL1 cells. Four days later, the mice were treated with 8 microg bsAb G2 (anti-CD3 x anti-Thy-1.2) or 10 microg (+10 microg, day 6) bsAb BiC (anti-CD3 x anti-I-Ad), respectively. These combinations guaranteed exclusive binding of the bsAbs target arms to tumor cells, leaving the surrounding, donor-type hematopoietic cells unbound. Compared with the parental antibodies, the bsAbs markedly reduced tumor mortality. Between 34% and 83% of mice survived in the bsAb groups compared with 0% of the control groups treated with parental antibodies, clearly documenting the benefit of the redirection principle. Furthermore, cytokine release (interleukin-6) after anti-CD3 antibody or bsAb treatment was decreased by administering a low-dose antibody preinjection. We have shown (1) that 6 weeks after BMT, when donor T-cell reconstitution is still in progress, T-cell-redirecting bsAb are clearly superior to parental antibodies in terms of tumor cell elimination; and (2) that the polymorphism of a common antigen such as Thy-1 or a clinically more relevant target antigen such as MHC class II can be used as an operational tumor-specific antigen after allogeneic BMT.
尽管化疗和骨髓移植（BMT）的程序有所改进，但在过去十年中，BMT后白血病的复发率一直相当稳定。用单克隆或双特异性抗体（bsAb）进行免疫治疗是改善这种情况的一种有前景的方法，但由于大多数肿瘤缺乏肿瘤特异性抗原而受到阻碍。为了规避这个问题，我们开发了一种新的肿瘤特异性方法，其中双特异性抗体通过将供体T细胞重定向到肿瘤细胞上的受体特异性抗原，利用异基因BMT后的嵌合现象。使用T细胞淋巴瘤（ST-1）和B细胞淋巴瘤（BCL1）建立了两种不同的白血病复发模型，以评估这种治疗的效果。在这些实验中，受照射的BALB/c（Thy-1.2+，I-Ad）小鼠在预防移植物抗宿主病的单克隆抗体保护下，移植C57BL/6 Thy-1.1（I-Ab）骨髓细胞。BMT后45天，给嵌合小鼠注射2×10⁴受体型、Thy-1.2+、CD3-的ST-1细胞或主要组织相容性复合体（MHC）II类+（I-Ad）的BCL1细胞。4天后，分别用8μg bsAb G2（抗CD3×抗Thy-1.2）或10μg（第6天加10μg）bsAb BiC（抗CD3×抗I-Ad）治疗小鼠。这些组合保证了bsAb的靶向臂与肿瘤细胞的特异性结合，使周围的供体型造血细胞不被结合。与亲本抗体相比，bsAb显著降低了肿瘤死亡率。bsAb组中有34%至83%的小鼠存活，而用亲本抗体治疗的对照组小鼠存活率为0%，清楚地证明了重定向原理的益处。此外，通过预先注射低剂量抗体，抗CD3抗体或bsAb治疗后的细胞因子释放（白细胞介素-6）减少。我们已经证明：（1）BMT后6周，当供体T细胞重建仍在进行时，重定向T细胞的bsAb在消除肿瘤细胞方面明显优于亲本抗体；（2）在异基因BMT后，常见抗原如Thy-1或临床上更相关的靶抗原如MHC II类的多态性可作为可操作的肿瘤特异性抗原。
