Antitumor effects of a bispecific antibody targeting CA19-9 antigen and CD16.
Antitumor effects of a bispecific antibody targeting CA19-9 antigen and CD16.
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发表时间：
1992-10
期刊：
影响因子：
11.2
通讯作者：
I. Garcia de Palazzo;M. Holmes;Ç. Gerçel-Taylor;L. Weiner
中科院分区：
文献类型：
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作者：
I. Garcia de Palazzo;M. Holmes;Ç. Gerçel-Taylor;L. Weiner
靶向肿瘤和Fc γ RIII（CD 16）的双特异性鼠单克隆抗体可通过大颗粒淋巴细胞促进相关肿瘤溶解。为了使这些抗体在临床上有用，它们的性质应该在体内保持，其中可能遇到竞争性人免疫球蛋白、脱落靶抗原和脱落CD 16。至少，双特异性抗体的抗肿瘤作用应保留在全血中。此外，肿瘤裂解的增强应通过证明双特异性抗体重靶向效应细胞浸润和介导机化肿瘤裂解的能力来反映。如果证实了这些特征，并且有证据表明基于双特异性抗体的疗法在相关动物模型中的体内功效，则将保证此类抗体的进一步临床开发。在本报告中，CL 158双特异性抗体上清液介导单层生长的SW 948肿瘤裂解的能力显示在白细胞介素2活化的全血存在下得以保留。当SW 948细胞在体外生长为多细胞人肿瘤球体时，与白细胞介素2激活的淋巴细胞（LAK细胞）和CL 158孵育导致结构性和广泛的坏死。这依赖于CL 158，并且对合并的人免疫球蛋白或白细胞介素2暴露的全血的竞争具有抗性。这些作用不被CL 158的亲本克隆产生的单特异性抗体促进，并且当使用介导常规抗体依赖性细胞毒性的CA 19 -9抗体的IgG 2a变体代替其双特异性衍生物时未观察到。为了检查基于双特异性抗体的治疗对体内肿瘤的功效，将携带早期s.c.用白细胞介素2连续5天处理SW 948异种移植物，并补充三次静脉内注射10（7）个人LAK细胞和各种抗体。用LAK细胞治疗携带SW 948肿瘤的小鼠并不延缓肿瘤生长，但当加入CL 158时，观察到肿瘤生长的显著延迟。肿瘤生长延迟需要用LAK细胞和双特异性抗体治疗。用CA 19 -9抗体的IgG 2a变体单独或与LAK细胞一起治疗对肿瘤生长没有影响。虽然这些抗肿瘤作用的机制需要进一步研究，但很明显，人LAK细胞治疗早期建立的皮下接种动物，通过添加具有相关结合特征的双特异性抗体，可以增强对肿瘤的抑制作用。当与CA 19 -9单克隆抗体的IgG 2a同种型变体相比时，该双特异性抗体提供了在生理条件下保留活性、体外浸润和破坏组织化肿瘤以及在相关异种移植模型中的抗肿瘤作用的优点。（400字处截断摘要）
Bispecific murine monoclonal antibodies that target tumor and Fc gamma RIII (CD16) can promote relevant tumor lysis by large granular lymphocytes. For these antibodies to be clinically useful, their properties should be maintained in vivo, where competing human immunoglobulin, shed target antigen, and shed CD16 may be encountered. At a minimum, bispecific antibody antitumor effects should be preserved in whole blood. Furthermore, potentiation of tumor lysis should be reflected by demonstrating the ability of bispecific antibody-retargeted effector cells to infiltrate and mediate lysis of organized tumor. If these characteristics are demonstrated, and there is evidence of in vivo efficacy of bispecific antibody-based therapy in a relevant animal model, further clinical development of such antibodies would be warranted. In this report the ability of CL158 bispecific antibody supernatants to mediate lysis of SW948 tumor growing in monolayer is shown to be preserved in the presence of interleukin 2-activated whole blood. When SW948 cells were grown in vitro as multicellular human tumor spheroids, incubation with interleukin 2-activated lymphocytes (LAK cells) and CL158 led to structural and widespread necrosis. This was dependent on CL158 and resistant to competition by pooled human immunoglobulin or interleukin 2-exposed whole blood. These effects were not promoted by the monospecific antibodies produced by the parent clones of CL158 and were not observed when the IgG2a variant of CA19-9 antibody, which mediates conventional antibody-dependent cellular cytotoxicity, was used instead of its bispecific derivative. To examine the efficacy of bispecific antibody-based treatments on in vivo tumor, scid mice bearing early s.c. SW948 xenografts were treated with interleukin 2 for 5 consecutive days, supplemented by three i.v. injections of 10(7) human LAK cells and various antibodies. Treatment of mice bearing SW948 tumors with LAK cells did not retard tumor growth, but when CL158 was added, significant delays in tumor growth were observed. Tumor growth delay required treatment with both LAK cells and the bispecific antibody. Treatment with the IgG2a variant of CA19-9 antibody, alone or with LAK cells, had no effects on tumor growth. Although the mechanisms of these antitumor effects require further study, it is clear that human LAK cell treatment of animals bearing early, established s.c. tumors is enhanced by the addition of bispecific antibodies with relevant binding characteristics. When compared with the IgG2a isotype variant of CA19-9 monoclonal antibody, this bispecific antibody offers the advantages of preservation of activity in physiological conditions, infiltration and disruption of organized tumor in vitro, and antitumor effects in a relevant xenograft model.(ABSTRACT TRUNCATED AT 400 WORDS)