Green Shane K, Karlsson Mikael C I, Ravetch Jeffrey V, Kerbel Robert S
Molecular and Cellular Biology Research, Sunnybrook and Women's College Health Sciences Center, Toronto, Ontario, Canada, M4N 3M5.
Cancer Res. 2002 Dec 1;62(23):6891-900.
Resistance to antibody-based anticancer approaches has become of considerable interest because of the rapidly growing clinical use of several different monoclonal antibodies as therapeutic agents, coupled with the recent finding that their efficacy may be attributable in part to their participation in host antibody-dependent cellular cytotoxicity. In this proof-of-concept study, we demonstrate the novel ability of an antiadhesive antibody (SHE78-7), targeted at the potent homophilic cell adhesion molecule E-cadherin, to play a dual role as participant in, and sensitizing agent for, host immune-mediated antitumor activity. SHE78-7 disrupted preformed multicellular aggregates (spheroids) of HT29 colon carcinoma cells both in vitro and in vivo in an ascites tumor xenograft model, but had no direct antitumor effect in vitro. In vivo, however, i.p. injection of SHE78-7 significantly prolonged the survival of nude mice carrying established i.p. HT29 xenografts, most notably when injections were given biweekly. This antitumor effect was dependent on the antiadhesive effect of SHE78-7 and could be effectively recapitulated via treatment with a combination of nondisruptive anti-hMHC-I antibodies, capable of recruiting an F(c)-mediated immune response but ineffective as a monotherapy and antiadhesive F(ab')(2) fragments of SHE78-7. Furthermore, additional therapy experiments using such F(ab')(2) fragments, or mice lacking activating F(c)gammaRIII receptors or inhibitory F(c)gammaRIIB, unequivocally indicated a role for host antibody-dependent cellular cytotoxicity, mediated by F(c)gammaRIII and negatively regulated by F(c)gammaRIIB. Taken together, the results suggest a possible means of improving antibody-based therapies of cancer, namely targeting antigens, selectively expressed or up-regulated by target cancer cells, which mediate cell-cell adhesive functions.
由于几种不同的单克隆抗体作为治疗药物在临床上的迅速广泛应用，以及最近发现它们的疗效可能部分归因于其参与宿主抗体依赖性细胞毒性作用，因此对基于抗体的抗癌方法的耐药性已成为相当受关注的问题。在这项概念验证研究中，我们证明了一种抗粘附抗体（SHE78-7）具有新的能力，该抗体靶向强效的同源性细胞粘附分子E-钙粘蛋白，可作为宿主免疫介导的抗肿瘤活性的参与者和致敏剂发挥双重作用。SHE78-7在体外和体内的腹水肿瘤异种移植模型中均破坏了HT29结肠癌细胞预先形成的多细胞聚集体（球体），但在体外没有直接抗肿瘤作用。然而，在体内，腹腔注射SHE78-7显著延长了携带已建立的腹腔HT29异种移植物的裸鼠的存活时间，最显著的是每两周注射一次时。这种抗肿瘤作用依赖于SHE78-7的抗粘附作用，并且可以通过用非破坏性抗人MHC-I抗体的组合进行治疗有效地重现，这些抗体能够募集F(c)介导的免疫反应，但作为单一疗法无效，以及SHE78-7的抗粘附F(ab')(2)片段。此外，使用此类F(ab')(2)片段或缺乏激活型F(c)γRIII受体或抑制型F(c)γRIIB的小鼠进行的额外治疗实验明确表明，由F(c)γRIII介导并由F(c)γRIIB负调节的宿主抗体依赖性细胞毒性起了作用。综上所述，结果表明了一种改善基于抗体的癌症治疗的可能方法，即靶向由靶癌细胞选择性表达或上调的、介导细胞间粘附功能的抗原。
