Prospects for the Application of Antibodies in Medicine
Prospects for the Application of Antibodies in Medicine
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5 Prospects for the Application of Antibodies in Medicine Herman Waldmann 1. Introduction The evolution of therapeutic agents in medicine has been based around a standard set of principles. These include: 1. 2. 3. 4. 5. 6. 7. 8.
A defined need. Specificity for the disease process to be controlled. Ease and cost of discovery and production. Stability and consistency of the product and its performance. Capacity to amplify the desired therapeutic with limited toxicity. Scope for patent protection and therefore profit opportunities. User-friendly application. Compatibility with regulatory requirements.
It is, therefore, not surprising that antibodies have significant appeal as therapeutics. Their remarkable specificity, well defined biochemical and biophysical properties, stability in adverse environments, natural capacity to seduce complement and cellular amplification events, and the abundant technology to ensure their high level expression in cell lines are all attractive features that have brought antibody diagnostics and therapeutics into prominence in the last 30 years, indeed ever since Köhler and Milstein made their momentous discovery. Acknowledging the many very fine chapters in this volume, I do not intend to duplicate information that the reader has or will be exposed to. Instead, I highlight emerging areas that may soon have sufficient impact to reverse the seemingly negative attitude of the biotechnology and pharmaceutical industries toward antibody therapy. I focus my attention on two issues. From: Methods in Molecular Medicine, Vol. 40: Diagnostic and Therapeutic Antibodies Edited by: A. J. T. George and C. E. Urch © Humana Press Inc., Totowa, NJ
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Table 1 Sources of Human Therapeutic Antibodies Chimeric antibodies Humanized antibodies Somatic hybrids from mice transgenic for human Ig genes Phage libraries from human lymphocytes Epstein-Barr virus immortalization Somatic hybrids with human lymphocytes Single-cell PCR
First, I discuss the immunogenicity problem, which has constrained thinking about antibodies as agents to be used on only a limited number of occasions in the individual patient. Second, I consider the opportunities for treatment of certain diseases, where antibodies may be used as short term therapy to gain long-term effects. 2. The Immunogenicity Problem 2.1. Introduction It has been recognized for some time, and it is not surprising that rodent antibodies are immunogenic in human patients. The consequence of this is the neutralization of the therapeutic agent and difficulty in readministration because of the unpredictable pharmacokinetics and risks of hypersensitivity reactions. For this reason it has been generally accepted that antibodies should be selected or engineered to be as “human” as possible. Table 1 lists some ways in which “human” antibodies may be derived. Some very amusing discussions have taken place claiming that certain forms of antibody are more human than others. This has led to major misconceptions that have been valuable for stock prices but
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