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Antibody catalysis: Biochemistry, immunology, pathology
Immunology Letters 103 (2006) 1–2
Editorial
Antibody catalysis: Biochemistry, immunology, pathology
The discovery of catalytic antibodies, otherwise known as antibody–enzymes or abzymes, was a revolutionary event that created new interfaces between chemistry, biochemistry, immunology, and pathology. The general concept of complementarity introduced in life sciences by Fischer [1] explains the driving force in various biological processes including genetic machinery, enzyme catalysis, ligand–receptor interaction, and antibody–antigen recognition. The creation of abzymes as a new class of biocatalysts is fundamentally dependent on intrinsic ability of immunoglobulins to produce complementary “molecular imprints” using the hypervariability of complementarity determining regions (CDR). These “catalytic imprints” can be made from stable chemical analogs of the transition state (TSA) of the enzyme reaction as outlined by Pauling [2] and Jencks [3]. This approach was experimentally first realized with polyclonal antibodies [4], but later and more effectively with monoclonals [5,6]. The concept was then extended by the groups of Lerner and Shultz at the Scripps Research Institute to a variety of chemical reactions, even in kinetically unfavorable conditions [7]. This coming of age permitted abzymes to be recognized as a tool for catalyzing reactions for which there was no effective enzyme analog. It was thus possible to develop biocatalysts with new functions, previously unknown for common enzymes, which can be profitably applied to novel strategies. A spectacular example is provided by abzyme-mediated cocaine-degrading reaction [8]. This abzyme, which is active both in vitro and in vivo, may be considered as the first attempt to make a “catalytic vaccine”. An alternative way to create abzymes is based on the immunological network hypothesis of Jerne [9]. This model provides a theoretical and practical basis for attempting to stimulate the formation an of anti-idiotypic antibody repertoire against the active site of an immunizing enzyme [10–12]. In both cases one tries to mimic a highly evolved enzymatic function by selecting antibody catalysts from a vast repertoire of immunoglobulins generated either by hybridoma or genetic library techniques. After the first publications on the autoantibody-mediated degradation of antigen [13,14] many laboratories concentrated on pathophysiological aspects of abzymology. As one result, it was recently shown that abzyme-mediated generation of peroxide and ozone represented a previously unknown biological pathway for killing of bacteria [15]. 0165-2478/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.imlet.2005.10.012
The spirit of enthusiasm that marked the beginning of the abzyme “era” [16] has changed to one of profound pessimism caused by a variety of fundamental problems in the field. The first involves the intrinsic properties of an antibody-based biocatalyst that can mimic the “recognition” properties of highly evolved enzymes but not their dynamics. This is the basis for the modest accelerating capacities of abzymes and for major problems with product inhibition. Many efforts, most of which were only modestly effective, were then made to design and to synthesize appropriate haptens for immunization as well as for screening catalytically active monoclonal or recombinant antibodies. The second crucial problem that may be described as a “fight with enzyme contamination” has triggered investigators to design numerous controls for newly induced or naturally occurring abzyme activity. The goal of this issue is to show the scientific community that the field is still promising and the “general pessimism” can be replaced by “pragmatic realism”. One of the main biomedical tasks of the field is to follow the many kinds of antibody-binding therapies currently under development in major pharmaceutical companies. Any efforts that are successful in bringing even 10–20% catalytic turnover to the adopted therapeutic antibody “binder” may be commercially acceptable. The advantage of the abzyme field is the opportunity to make “catalytic vaccines” targeted against low molecular weight “poisoning” molecules such as narcotics, pesticides, and drugs, as well as against bacterial and viral proteins. All the advantages associated with the “antibody nature” of these biocatalysts make abzyme therapy potentially attractive for R&D—their relative stability in the circulation, high specificity, and widespread experience in genetic manipulations, and ease of expression as well as a long history of using antibody molecules for treatment of a variety of human conditions. Although the striking achievements in disease-associated abzyme studies seem obvious [17,18], many of the basic aspects remain enigmatic. The list of natural antigens that appear to function as substrates for autoantibodies is increasing, but examples that may be unequivocally tied to pathophysiological mechanisms of a disease process await critical investigation. I do hope that this issue to some extent helps update our knowledge in the field by presenting a spectrum of perspec-
2
Editorial / Immunology Letters 103 (2006) 1–2
tives ranging from very basic reviews to concrete experimental achievements. References [1] Fischer E. Einfluss der Configuration auf die Wirkung der Enzyme. Berichte Deutsh Chem Ges 1894;27:2968. [2] Pauling L. Chemical achievement and hope for the future. Am Sci 1948;36:50–8. [3] Jencks WP, editor. Catalysis in chemistry and enzymology. New York/London: McGraw-Hill; 1969. [4] Raso V, Stollar BD. The antibody–enzyme analogy. Comparison of enzymes and antibodies specific for phosphopyridoxyltyrosine. Biochemistry 1975;14:591–9. [5] Kohen F, Kim JB, Lindner HR, Eshhar Z, Green B. Monoclonal immunoglobulin G augments hydrolysis of an ester of the homologous hapten: an esterase-like activity of the antibody-containing site? FEBS Lett 1980;111:427–31. [6] Tramontano A, Janda KD, Lerner RA. Catalytic antibodies. Science 1986;234:1566–70. [7] Schultz PG, Yin J, Lerner RA. The chemistry of the antibody molecule. Angew Chem Int Ed Engl 2002;41:4427–37. [8] Mets B, Winger G, Cabrera C, Seo S, Jamdar S, Yang G, et al. A catalytic antibody against cocaine prevents cocaine’s reinforcing and toxic effects in rats. Proc Natl Acad Sci USA 1998;95:10176–81. [9] Jerne NK. Towards a network theory of the immune system. Ann Immunol (Paris) 1974;125C:373–89. [10] Avalle B, Friboulet A, Thomas D. Catalysis by anti-idiotypic antibodies. Chem Immunol 2000;77:80–8. [11] Kolesnikov AV, Kozyr AV, Alexandrova ES, Koralewski F, Demin AV, Titov MI, et al. Enzyme mimicry by the antiidiotypic antibody approach. Proc Natl Acad Sci USA 2000;97:13526–31.
[12] Pillet D, Paon M, Vorobiev II, Gabibov AG, Thomas D, Friboulet A. Idiotypic network mimicry and antibody catalysis: lessons for the elicitation of efficient anti-idiotypic protease antibodies. J Immunol Methods 2002;269:5–12. [13] Paul S, Volle DJ, Beach CM, Johnson DR, Powell MJ, Massey RJ. Catalytic hydrolysis of vasoactive intestinal peptide by human autoantibody. Science 1989;244:1158–62. [14] Shuster AM, Gololobov GV, Kvashuk OA, Bogomolova AE, Smirnov IV, Gabibov AG. DNA hydrolyzing autoantibodies. Science 1992;256:665–7. [15] Wentworth Jr P, McDunn JE, Wentworth AD, Takeuchi C, Nieva J, Jones T, et al. Evidence for antibody-catalyzed ozone formation in bacterial killing and inflammation. Science 2002;298:2195–9. [16] Benkovic SJ. Catalytic antibodies. Annu Rev Biochem 1992;61:29– 54. [17] Lacroix-Desmazes S, Bayry J, Kaveri SV, Hayon-Sonsino D, Thorenoor N, Charpentier J, et al. High levels of catalytic antibodies correlate with favorable outcome in sepsis. Proc Natl Acad Sci USA 2005;102:4109–13. [18] Lacroix-Desmazes S, Bayry J, Misra N, Horn MP, Villard S, Pashov A, et al. The prevalence of proteolytic antibodies against factor VIII in hemophilia A. N Engl J Med 2002;346:662–7.
Alexander Gabibov Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation E-mail address: [email protected] 11 October 2005 Available online 8 November 2005
Editorial
Antibody catalysis: Biochemistry, immunology, pathology
The discovery of catalytic antibodies, otherwise known as antibody–enzymes or abzymes, was a revolutionary event that created new interfaces between chemistry, biochemistry, immunology, and pathology. The general concept of complementarity introduced in life sciences by Fischer [1] explains the driving force in various biological processes including genetic machinery, enzyme catalysis, ligand–receptor interaction, and antibody–antigen recognition. The creation of abzymes as a new class of biocatalysts is fundamentally dependent on intrinsic ability of immunoglobulins to produce complementary “molecular imprints” using the hypervariability of complementarity determining regions (CDR). These “catalytic imprints” can be made from stable chemical analogs of the transition state (TSA) of the enzyme reaction as outlined by Pauling [2] and Jencks [3]. This approach was experimentally first realized with polyclonal antibodies [4], but later and more effectively with monoclonals [5,6]. The concept was then extended by the groups of Lerner and Shultz at the Scripps Research Institute to a variety of chemical reactions, even in kinetically unfavorable conditions [7]. This coming of age permitted abzymes to be recognized as a tool for catalyzing reactions for which there was no effective enzyme analog. It was thus possible to develop biocatalysts with new functions, previously unknown for common enzymes, which can be profitably applied to novel strategies. A spectacular example is provided by abzyme-mediated cocaine-degrading reaction [8]. This abzyme, which is active both in vitro and in vivo, may be considered as the first attempt to make a “catalytic vaccine”. An alternative way to create abzymes is based on the immunological network hypothesis of Jerne [9]. This model provides a theoretical and practical basis for attempting to stimulate the formation an of anti-idiotypic antibody repertoire against the active site of an immunizing enzyme [10–12]. In both cases one tries to mimic a highly evolved enzymatic function by selecting antibody catalysts from a vast repertoire of immunoglobulins generated either by hybridoma or genetic library techniques. After the first publications on the autoantibody-mediated degradation of antigen [13,14] many laboratories concentrated on pathophysiological aspects of abzymology. As one result, it was recently shown that abzyme-mediated generation of peroxide and ozone represented a previously unknown biological pathway for killing of bacteria [15]. 0165-2478/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.imlet.2005.10.012
The spirit of enthusiasm that marked the beginning of the abzyme “era” [16] has changed to one of profound pessimism caused by a variety of fundamental problems in the field. The first involves the intrinsic properties of an antibody-based biocatalyst that can mimic the “recognition” properties of highly evolved enzymes but not their dynamics. This is the basis for the modest accelerating capacities of abzymes and for major problems with product inhibition. Many efforts, most of which were only modestly effective, were then made to design and to synthesize appropriate haptens for immunization as well as for screening catalytically active monoclonal or recombinant antibodies. The second crucial problem that may be described as a “fight with enzyme contamination” has triggered investigators to design numerous controls for newly induced or naturally occurring abzyme activity. The goal of this issue is to show the scientific community that the field is still promising and the “general pessimism” can be replaced by “pragmatic realism”. One of the main biomedical tasks of the field is to follow the many kinds of antibody-binding therapies currently under development in major pharmaceutical companies. Any efforts that are successful in bringing even 10–20% catalytic turnover to the adopted therapeutic antibody “binder” may be commercially acceptable. The advantage of the abzyme field is the opportunity to make “catalytic vaccines” targeted against low molecular weight “poisoning” molecules such as narcotics, pesticides, and drugs, as well as against bacterial and viral proteins. All the advantages associated with the “antibody nature” of these biocatalysts make abzyme therapy potentially attractive for R&D—their relative stability in the circulation, high specificity, and widespread experience in genetic manipulations, and ease of expression as well as a long history of using antibody molecules for treatment of a variety of human conditions. Although the striking achievements in disease-associated abzyme studies seem obvious [17,18], many of the basic aspects remain enigmatic. The list of natural antigens that appear to function as substrates for autoantibodies is increasing, but examples that may be unequivocally tied to pathophysiological mechanisms of a disease process await critical investigation. I do hope that this issue to some extent helps update our knowledge in the field by presenting a spectrum of perspec-
2
Editorial / Immunology Letters 103 (2006) 1–2
tives ranging from very basic reviews to concrete experimental achievements. References [1] Fischer E. Einfluss der Configuration auf die Wirkung der Enzyme. Berichte Deutsh Chem Ges 1894;27:2968. [2] Pauling L. Chemical achievement and hope for the future. Am Sci 1948;36:50–8. [3] Jencks WP, editor. Catalysis in chemistry and enzymology. New York/London: McGraw-Hill; 1969. [4] Raso V, Stollar BD. The antibody–enzyme analogy. Comparison of enzymes and antibodies specific for phosphopyridoxyltyrosine. Biochemistry 1975;14:591–9. [5] Kohen F, Kim JB, Lindner HR, Eshhar Z, Green B. Monoclonal immunoglobulin G augments hydrolysis of an ester of the homologous hapten: an esterase-like activity of the antibody-containing site? FEBS Lett 1980;111:427–31. [6] Tramontano A, Janda KD, Lerner RA. Catalytic antibodies. Science 1986;234:1566–70. [7] Schultz PG, Yin J, Lerner RA. The chemistry of the antibody molecule. Angew Chem Int Ed Engl 2002;41:4427–37. [8] Mets B, Winger G, Cabrera C, Seo S, Jamdar S, Yang G, et al. A catalytic antibody against cocaine prevents cocaine’s reinforcing and toxic effects in rats. Proc Natl Acad Sci USA 1998;95:10176–81. [9] Jerne NK. Towards a network theory of the immune system. Ann Immunol (Paris) 1974;125C:373–89. [10] Avalle B, Friboulet A, Thomas D. Catalysis by anti-idiotypic antibodies. Chem Immunol 2000;77:80–8. [11] Kolesnikov AV, Kozyr AV, Alexandrova ES, Koralewski F, Demin AV, Titov MI, et al. Enzyme mimicry by the antiidiotypic antibody approach. Proc Natl Acad Sci USA 2000;97:13526–31.
[12] Pillet D, Paon M, Vorobiev II, Gabibov AG, Thomas D, Friboulet A. Idiotypic network mimicry and antibody catalysis: lessons for the elicitation of efficient anti-idiotypic protease antibodies. J Immunol Methods 2002;269:5–12. [13] Paul S, Volle DJ, Beach CM, Johnson DR, Powell MJ, Massey RJ. Catalytic hydrolysis of vasoactive intestinal peptide by human autoantibody. Science 1989;244:1158–62. [14] Shuster AM, Gololobov GV, Kvashuk OA, Bogomolova AE, Smirnov IV, Gabibov AG. DNA hydrolyzing autoantibodies. Science 1992;256:665–7. [15] Wentworth Jr P, McDunn JE, Wentworth AD, Takeuchi C, Nieva J, Jones T, et al. Evidence for antibody-catalyzed ozone formation in bacterial killing and inflammation. Science 2002;298:2195–9. [16] Benkovic SJ. Catalytic antibodies. Annu Rev Biochem 1992;61:29– 54. [17] Lacroix-Desmazes S, Bayry J, Kaveri SV, Hayon-Sonsino D, Thorenoor N, Charpentier J, et al. High levels of catalytic antibodies correlate with favorable outcome in sepsis. Proc Natl Acad Sci USA 2005;102:4109–13. [18] Lacroix-Desmazes S, Bayry J, Misra N, Horn MP, Villard S, Pashov A, et al. The prevalence of proteolytic antibodies against factor VIII in hemophilia A. N Engl J Med 2002;346:662–7.
Alexander Gabibov Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation E-mail address: [email protected] 11 October 2005 Available online 8 November 2005