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In vivo production of therapeutic antibodies byengineered cells for immunotherapy of cancer andviral diseases

机译：通过工程化细胞体内生产治疗性抗体，用于癌症和病毒性疾病的免疫治疗

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Our recently developed ability to produce human monoclonal antibodies, together with that of reshaping antibody molecules, offers new tools for treating a number of human diseases. Direct injection of purified antibodies, or of antibody-related molecules, to patients would, however, not always be possible or desirable. This is especially true in the case of long-term therapies for at least two reasons. One is the high cost of antibodies certified for human use. The other is the possibility of neutralizing anti-idiotypic immune responses as a result of repeated injection of massive doses of antibody. In vivo production of therapeutic antibodies through either genetic modification of patients' cells or implantation of antibody-producing cells might overcome both of these hurdles. Several cell types suitable for use in cell/gene therapy protocols, such as skin fibroblasts, keratinocytes, myogenic cells and hepatocytes, are capable of producing monoclonal antibodies in vitro upon gene transfer. Furthermore, the grafting of engineered myogenic cells permits the long-term systemic delivery of recombinant antibodies in immunocompetent mice. Importantly, antibodies produced both in vitro and in vivo, retain the specificity and the affinity of the parental antibody and no anti-idiotypic response is detected in mice producing ectopic antibodies. Long-term systemic delivery of such antibodies into mice can also be achieved through the implantation of antibody-producing cells encapsulated into a new biocompatible material, cellulose sulphate. Importantly, no inflammation occurs at capsule implantation sites over periods as long as 10 months. Moreover, no anti-idiotypic response develops against antibodies released by encapsulated cells. Encapsulation of antibody-producing cells in immunoprotective devices should offer multiple advantages over genetic modification of patients' cells. These include protection against immune cells of treated individuals, the possibility of easy removal of implanted cells as well as that of implantation of non-autologous cells. Taken together, these observations demonstrate that long-term in vivo production and systemic delivery of monoclonal antibodies is technically feasible. Application of this technology to the treatment of various viral and autoimmune diseases as well as that of cancer is currently underway.
机译：我们最近开发的产生人类单克隆抗体的能力以及重塑抗体分子的能力，为治疗多种人类疾病提供了新的工具。然而，将纯化的抗体或抗体相关分子直接注射给患者并非总是可能或需要的。至少有两个原因，在长期治疗的情况下尤其如此。一种是认证为人类使用的抗体的高成本。另一个是由于反复注射大量抗体而中和抗独特型免疫反应的可能性。通过对患者细胞进行基因修饰或植入产生抗体的细胞来体内产生治疗性抗体可能会克服这两个障碍。适用于细胞/基因治疗方案的几种细胞类型，例如皮肤成纤维细胞，角质形成细胞，成肌细胞和肝细胞，能够在基因转移后在体外产生单克隆抗体。此外，工程化的成肌细胞的移植允许在免疫活性小鼠中长期全身递送重组抗体。重要的是，在体外和体内产生的抗体都保留了亲本抗体的特异性和亲和力，并且在产生异位抗体的小鼠中未检测到抗独特型反应。也可以通过植入包裹在新的生物相容性材料硫酸纤维素中的抗体产生细胞来实现将此类抗体长期全身性地转移到小鼠体内。重要的是，在长达10个月的时间内，胶囊植入部位不会发生炎症。此外，针对包囊细胞释放的抗体没有抗独特型反应。与患者细胞的基因修饰相比，将抗体产生细胞封装在免疫保护装置中应提供多种优势。这些措施包括针对被治疗个体的免疫细胞的保护，容易去除植入细胞的可能性以及植入非自体细胞的可能性。综上所述，这些观察结果表明，单克隆抗体的长期体内生产和全身递送在技术上是可行的。目前正在将该技术用于治疗各种病毒和自身免疫性疾病以及癌症。

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