Recombinant Antibodies for Immunotherapy

Book Reviews: The potential of antibodies as magic bullets for curing disease has excited the imagination of medical researchers ever since this phrase was first coined by Paul Ehrlich about a century ago. Seventy-five years after the publication of Ehrlich’s side-chain theory to explain antibody-antigen reactions in 1900, Georges Ko¨hler and Ce´sar Milstein invented a means of cloning antibodies with defined specificity that paved the way for major advances in cell biological and clinical research. They were awarded the Nobel Prize in Medicine in 1984 for this ground-breaking research. In 1986, the first monoclonal antibody, the murine mAb OKT3 for preventing transplant rejection, was approved for clinical use, and although many other murine mAbs were subsequently investigated as therapeutic agents, most of them had a disappointing clinical profile largely due to their immunogenicity. This situation improved dramatically with the advent of techniques to humanize existing mAbs, followed by technologies that sought to imitate the generation of specific antibodies by the immune systemin vitro. For example, the expression of antibody fragments in E. coli using bacterial leader sequences and the use of phage display and later ribosome display facilitated the selection of specific human antibodies from extremely large libraries. The process of somatic hypermutation to increase antibody affinity was mimicked by introducing random mutations. Another major advance for obtaining human antibodies was the creation of transgenic mice carrying a large part of the human antibody gene repertoire, which could be used to produce human antibodies by standard hybridoma technology. The success of these novel technologies resulted in a first generation of recombinant antibodies that now account for a large proportion of the market for biopharmaceuticals, with annual growth rates of almost 40%.

Therapeutic antibodies for cancer rely to a large extent on the recruitment of other elements in the immune system for their effect; very few of them function as magic bullets in the sense of ‘‘target and destroy.’’ For example, although antibody binding to a specific epitope of a cell surface receptor can directly induce strong apoptotic signals, the effect is usually amplified by cross-linking of the antibody Fc domains through binding to Fc receptors on immune effector cells such as macrophages and natural killer cells. Concomitantly, the immune effector cells are activated by the engagement of the Fc receptors, resulting in an attack on the cells to which they are bound, a process known as antibody-dependent cell cytolysis (ADCC). The Fc domains can also activate the complement system, causing complement-dependent cytolysis (CDC). To what extent cell lysis is caused by direct binding and how much is due to the recruitment of immune effector cells and complement is difficult to quantify, especially in an in vivo system, and in many cases the mechanism of action of antitumor antibodies remains ill defined. For the action of most cytolytic antibodies, all three mechanisms are probably involved to a lesser or greater extent. Furthermore, recent findings suggest that ADCC also contributes to the efficacy of those antibodies that were previously thought to cause tumor regression solely by blocking the ligandbinding site of growth hormone receptors.

Bibliographical Data of Recombinant Antibodies for Immunotherapy

Reference Type: Book
Record Number: xx
Author: Melvyn Little PhD
Year: 2009
Place Published: Cambridge, England
Publisher: Cambridge University Press
Number of Pages: 434
Edition: 1st
ISBN -10: 0521887321
ISBN-13: 978-0521887328
Kindle Available: ASIN- B014YY8BXU
Buy: Get it on Amazon

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