Animals are genetically manipulated to harbor human immunoglobulin loci, and the animal’s endogenous immunoglobulin loci are inactivated. Upon immunization, these transgenic animals produce human antibodies, and pooled sera might be used to prepare human polyclonal antibody therapeutics.
3.Recombinant polyclonal antibodies from transgenic animals Polyclonal antibodies, representing animal or human serum-derived cocktails of mAbs, are marketed for various indications, especially in infectious diseases. By binding to multiple epitopes, polyclonal antibodies recruit Fc-region-dependent effector mechanisms that, in concert, eliminate the target and diminish the ability of the target to escape eradication by mutating target epitopes.
For example, amino acids in the Fc region have been modified to achieve >2 orders of magnitude enhancement of in vitro effector functions of the antitumor mAbs rituximab and trastuzumab .In another approach, genetic engineering of the glycosylation pathways of two conventional production cell lines, the yeast Pichia Pastoris and the aquatic plant Lemna minor, has yielded mAbs with altered Fc-glycosylation patterns with superior tumor-cell killing activity.
Introduction
The therapeutic and commercial success of monoclonal antibodies (mAbs) has inspired innovative approaches aimed at increasing their potency and broadening their applicability. Among these, cocktails of recombinant human mAbs are a logical next step because they combine the technological advances made in the field of antibody engineering with the notion that the ingredients of polyclonal-antibody preparations act in concert to optimally exert and recruit effector functions.
Antibody cocktails: next generation biopharmaceuticals with improved potency
2007 Trends in Biotechnology
制药工程王思佳2010207017
Notions
单克隆抗体：抗体主要由B淋巴细胞合成。每个B淋巴细胞有合成 单克隆抗体 一种抗体的遗传基因。动物脾脏有上百万种不同的B淋巴细胞 系，含遗传基因不同的B淋巴细胞合成不同的抗体。当机体受 抗原刺激时，抗原分子上的许多决定簇分别激活各个具有不同 基因的B细胞。被激活的B细胞分裂增殖形成该细胞的子孙， 即克隆由许多个被激活B细胞的分裂增殖形成多克隆，并合成 多种抗体。如果能选出一个制造一种专一抗体的细胞进行培养， 就可得到由单细胞经分裂增殖而形成细胞群，即单克隆。单克 隆细胞将合成一种决定簇的抗体，称为单克隆抗体。 多克隆抗体：由多种抗原决定簇刺激机体，相应地就产生各种各 多克隆抗体 样的单克隆抗体，这些单克隆抗体混杂在一起就是多克隆抗体， 机体内所产生的抗体就是多克隆抗体；除了抗原决定簇的多样 性以外，同样一类抗原决定簇，也可刺激机体产生IgG、IgM、 IgA、IgE和IgD等五类抗体。
1.Shortage of hyperimmune human sera for only a restricted number of diseases and unwanted side effects resulting from infusing animal proteins in humans. 2.Batch-to-batch variation, risk of disease transmission and precise control over the antibody composition of polyclonal sera, are not resolved. 3.In polyclonal sera, only a small fraction of the IgG molecules is specific for the target molecule, resulting in the necessity of applying large quantities of protein. 4.Even the fraction of target-binding antibodies might contain species that do not contribute to the desired biological effect and that in fact compete with IgG species that bind to ‘functional’ epitopes involved in, for example, virus neutralization or recruitment of immune-effector functions.
Contents
1. Setting the stage for innovative antibody therapeutics 2. Antibody-constant-region (also known as the fragment crystallizable (Fc) region) engineering yields more-potent mAbs 3. Recombinant polyclonal antibodies from transgenic animals 4. Recombinant antibody cocktails from monoclonal and polyclonal cell lines 5. Effector mechanisms of cocktails of mAbs:what might be expected?
In spite of these advances, the moderate clinical efficacy of mAbs in some diseases and the lagging application of mAbs in others, such as infectious diseases, has left considerable room for improvement. Here we will describe innovative approaches toward improving therapeutic antibodies, and places an emphasis on antibody cocktails that seek to mimic（模拟lonal-antibody preparations while preserving the pharmaceutical virtues of mAbs.
1. Setting the stage for innovative antibody therapeutics Technologies for selection and engineering of therapeutic mAbs are now well established, facilitating the design of tailor made biopharmaceuticals with exquisite specificity and unprecedented affinity. The fact that 18 marketed mAb drugs had combined sales totaling $14 billion in 2005 is a testament to the success of mAbs as the fastest growing class of therapeutics; large pharmaceutical companies continue to enter the stage by striking significant licensing deals or by acquiring biotechnology companies with mAb product pipelines and proprietary technology.