Abbott Bioresearch Center, Worcester, MA, USA.
MAbs. 2010 May-Jun;2(3):221-32. doi: 10.4161/mabs.2.3.11788. Epub 2010 May 16.
Drug development from early discovery to late stage commercialization is a long arduous process where a number of factors are taken into consideration when deciding on a particular immunoglobulin isotype for a therapeutic purpose. There are no general rules for which isotype is selected; however, prior experiences, effector function and the specific therapy targeted, as well as extensive testing early in development help in pairing the number of candidates. Over 20 monoclonal antibodies are FDA-approved, and most are IgG1 isotype, although a number of non-IgG1 molecules have been approved recently and the number in development is on the rise. Analytical techniques that examine the physicochemical properties of a molecule provide vital information on the stability and efficacy of candidate antibody therapeutics, but most of these studies are conducted using standard buffers and under well defined storage conditions. It has recently become apparent that analysis of antibody therapeutics recovered after circulation in blood show altered physicochemical characteristics, and in many instances therapeutic molecules recovered from serum show lower potency. This review examines some of these studies, with a focus on the physicochemical changes observed in the molecules. Technologies that can facilitate rapid screening of candidate antibody therapeutics directly from blood are highlighted. The facts indicate that antibody therapeutic development programs must incorporate understanding of the basic biology of the isotype and its stability in serum, which is the intended environment of the therapeutic.
从早期发现到后期商业化，药物开发是一个漫长而艰巨的过程，在决定治疗目的的特定免疫球蛋白类型时需要考虑许多因素。没有选择特定同种型的一般规则；但是，先前的经验、效应功能和特定的治疗靶点，以及在早期开发过程中的广泛测试有助于配对候选者的数量。超过 20 种单克隆抗体已获得 FDA 批准，其中大多数为 IgG1 同种型，尽管最近已批准了一些非 IgG1 分子，并且开发中的数量正在增加。检查分子理化性质的分析技术为候选抗体治疗药物的稳定性和功效提供了重要信息，但这些研究大多是使用标准缓冲液和明确定义的储存条件进行的。最近已经明显的是，在血液中循环后回收的抗体治疗药物的分析显示出改变的理化特性，并且在许多情况下从血清中回收的治疗分子显示出较低的效力。这篇综述检查了其中的一些研究，重点是观察到的分子的理化变化。突出了可以直接从血液中快速筛选候选抗体治疗药物的技术。事实表明，抗体治疗药物开发计划必须包括对同种型的基本生物学及其在血清中的稳定性的理解，这是治疗药物的预期环境。
