Harman Benjamin C, Giles-Komar Jill, Rycyzyn Michael A
Biologics Research, Biotechnology Center of Excellence, Janssen Research and Development, PO Box 776, Welsh and McKean Roads, Spring House, PA 19477, USA.
Curr Drug Discov Technol. 2014 Mar;11(1):65-73. doi: 10.2174/15701638113109990036.
Since Kohler and Milstein developed the process of generating hybridomas by fusing antibody secreting B cells with an immortal myeloma cell line, the techniques used to develop monoclonal antibodies for use as human therapeutics have progressed significantly. Here, we will briefly review hybridoma technology and the evolution of therapeutic antibodies for the treatment of human disease. We will focus on the evolution of humanized mouse models for the generation of therapeutic human antibodies, comparing the early models, such as severe combined immunodeficient (SCID) mice which do not engraft human leukocytes well due to residual innate immunity, to the more recently developed models such as non-obese diabetic (NOD)/SCID IL-2Rγ-deficient mice in which numerous human hematopoietic lineages can be cultivated. Building on the identification of suitable host strains for the reconstitution of human immune cells, focus has now shifted onto humanizing the murine microenvironment in order to support human immune cell function. Although several recent studies have shown that the provision of human soluble factors can support maturation and function of human immune cells, particularly within the myeloid compartment, this does not appear to impact antibody production significantly. Moreover, models in which grafting of human tissues is performed to provide human microenvironments which support human leukocyte maturation do show improved humoral immune function, but require several surgical manipulations for generation of the model. Ultimately the most desirable scenario is to generate transgenic models that can be bred efficiently and express a sufficient number of human molecules to support functional human immune cells and several groups have made progress in making this idea a reality. These studies in the context of the generation of human antibodies will be discussed.
自从科勒（Kohler）和米尔斯坦（Milstein）通过将分泌抗体的B细胞与永生骨髓瘤细胞系融合开发出产生杂交瘤的方法以来，用于开发作为人类治疗药物的单克隆抗体的技术有了显著进展。在此，我们将简要回顾杂交瘤技术以及用于治疗人类疾病的治疗性抗体的发展历程。我们将重点关注用于产生治疗性人类抗体的人源化小鼠模型的发展，比较早期模型，如严重联合免疫缺陷（SCID）小鼠，由于残留的先天免疫，其不能很好地植入人类白细胞，与最近开发的模型，如非肥胖糖尿病（NOD）/SCID白细胞介素-2受体γ缺陷小鼠，在其中可以培养多种人类造血谱系。在确定了用于重建人类免疫细胞的合适宿主品系的基础上，现在的重点已转向人源化小鼠微环境以支持人类免疫细胞功能。尽管最近的几项研究表明，提供人类可溶性因子可以支持人类免疫细胞的成熟和功能，特别是在髓系区室中，但这似乎对抗体产生没有显著影响。此外，通过移植人类组织来提供支持人类白细胞成熟的人类微环境的模型确实显示出体液免疫功能有所改善，但需要进行几次外科手术来建立该模型。最终，最理想的情况是生成能够高效繁殖并表达足够数量人类分子以支持功能性人类免疫细胞的转基因模型，并且有几个研究小组在将这一想法变为现实方面取得了进展。将讨论在产生人类抗体背景下的这些研究。
