Foundation of Abzyme and Covalent Vaccination Approach

1. Abzyme basic science

• Discovery of naturally occurring catalytic antibodies (abzymes) by Paul et al in 1989 (1)

• Independent reproduction of naturally occurring abzymes by several groups (2-14)

• Identification by Paul group of abzyme covalent catalytic mechanism as an example of convergent evolution with classical serine protease family of enzymes (15)

• Independent reproduction of serine protease-like catalysis by antibodies by several groups (16- 21)

2.  Amyloid ß targeting by abzymes

• Discovery of cross-reactive amyloid ß-degrading abzymes by Sierks group (22) using catalytic antibody light chain subunits supplied by Paul group

• Discovery of abzyme clearance of amlyoid ß as a physiological mechanism in old age and Alzheimer’s patients by Paul group (23)

• Engineering of efficient amyloid ß degrading abzymes by Paul group (24)

• Independent demonstration of amyloid plaque removal from transgenic mouse brain by foregoing abzymes by Sigurdsson group (to be published)

• Task ahead: Establishing safety and efficacy of amyloid β degrading abzymes for treatment of Alzheimer’s disease in animals and humans

3.  Identifying the Achilles heel of HIV

• Discovery of antibodies from non-infected humans that bind 421-433 region of HIV gp120 weakly by Braun group (25) and Zouali group (26)

• Identification of increased levels of antibodies to this region in lupus patients by Shearer/Mozes group (27)

• Collaborative isolation of potent HIV neutralizing antibodies to this region from lupus patients by Paul group and Hanson group (28), identification of abzymes to this region by Paul group (29,30). 

• Discovery of abzymes and reversibly binding antibodies to 421-433 gp120 region in blood of long-term survivors of HIV infection by Paul group (31)

• Demonstration of neutralization of genetically diverse HIV strains by these antibodies by Hanson group and independent verification of neutralizing activity by Montefiori group and  Ochsenbauer group (31, unpublished) – designation of the 421-433 region as the Achilles heel of HIV

• Antibodies made available for non-profit research entities by Paul group

4.  Covalent vaccination approach

• Covalent immunization shown to induce abzymes and abzyme-like antibodies to HIV by Paul group (32-34)

• Similar covalent immunization approach independently used by others to induces abzymes with serine esterase (35) and aldolase-like  (36) enzymatic activities

• Prototype vaccine that induced HIV neutralizing abzymes-like antibodies directed to the 421-433 Achilles heel of HIV developed by Paul group (37)

• HIV neutralization by prototype vaccine-induced antibodies verified independently by Hanson group, Montefiori group (cited in ref 37) and Ochsenbauer group (unpublished)

• Task ahead: Effective HIV vaccination by focusing the immune response at the Achilles heel, maximizing the abzyme response (38)

 

References

1.  Paul, S., Volle, D. J., Beach, C. M., Johnson, D. R., Powell, M. J., and Massey, R. J. (1989) Catalytic hydrolysis of vasoactive intestinal peptide by human autoantibody. Science 244, 1158-1162

2.  Shuster, A. M., Gololobov, G. V., Kvashuk, O. A., Bogomolova, A. E., Smirnov, I. V., and Gabibov, A. G. (1992) DNA hydrolyzing autoantibodies. Science 256, 665-667

3.  Ponomarenko, N. A., Durova, O. M., Vorobiev, II, Aleksandrova, E. S., Telegin, G. B., Chamborant, O. G., Sidorik, L. L., Suchkov, S. V., Alekberova, Z. S., Gnuchev, N. V., and Gabibov, A. G. (2002) Catalytic antibodies in clinical and experimental pathology: human and mouse models. J Immunol Methods 269, 197-211

4.  Matsuura, K., Ikoma, S., Yoshida, K., and Sinohara, H. (1998) DNA-hydrolyzing activity of Bence Jones proteins. Biochem Biophys Res Commun 243, 719-721

5.  Lacroix-Desmazes, S., Moreau, A., Sooryanarayana, Bonnemain, C., Stieltjes, N., Pashov, A., Sultan, Y., Hoebeke, J., Kazatchkine, M. D., and Kaveri, S. V. (1999) Catalytic activity of antibodies against factor VIII in patients with hemophilia A. Nat Med 5, 1044-1047

6.  Lacroix-Desmazes, S., Bayry, J., Misra, N., Horn, M. P., Villard, S., Pashov, A., Stieltjes, N., d'Oiron, R., Saint-Remy, J. M., Hoebeke, J., Kazatchkine, M. D., Reinbolt, J., Mohanty, D., and Kaveri, S. V. (2002) The prevalence of proteolytic antibodies against factor VIII in hemophilia A. N Engl J Med 346, 662-667

7.  Uda, T., Hifumi, E., Ohara, K., and Zhou, Y. (2000) Catalytic activity of antibody light chain to gp41: a consideration of refolding in relation to activation mechanism. Chem Immunol 77, 18-32

8.  Hifumi, E., Morihara, F., Hatiuchi, K., Okuda, T., Nishizono, A., and Uda, T. (2008) Catalytic features and eradication ability of antibody light-chain UA15-L against Helicobacter pylori. J Biol Chem 283, 899-907

9.  Baranovskii, A. G., Ershova, N. A., Buneva, V. N., Kanyshkova, T. G., Mogelnitskii, A. S., Doronin, B. M., Boiko, A. N., Gusev, E. I., Favorova, O. O., and Nevinsky, G. A. (2001) Catalytic heterogeneity of polyclonal DNA-hydrolyzing antibodies from the sera of patients with multiple sclerosis. Immunol Lett 76, 163-167

10.  Ponomarenko, N. A., Durova, O. M., Vorobiev, II, Aleksandrova, E. S., Telegin, G. B., Chamborant, O. G., Sidorik, L. L., Suchkov, S. V., Alekberova, Z. S., Gnuchev, N. V., and Gabibov, A. G. (2002) Catalytic antibodies in clinical and experimental pathology: human and mouse models. J Immunol Methods 269, 197-211

11.  Hifumi, E., Hatiuchi, K., Okuda, T., Nishizono, A., Okamura, Y., and Uda, T. (2005) Specific degradation of H. pylori urease by a catalytic antibody light chain. Febs J 272, 4497-4505

12.  Polosukhina, D. I., Buneva, V. N., Doronin, B. M., Tyshkevich, O. B., Boiko, A. N., Gusev, E. I., Favorova, O. O., and Nevinsky, G. A. (2005) Hydrolysis of myelin basic protein by IgM and IgA antibodies from the sera of patients with multiple sclerosis. Med Sci Monit 11, BR266-272

13.  Odintsova, E. S., Buneva, V. N., and Nevinsky, G. A. (2005) Casein-hydrolyzing activity of sIgA antibodies from human milk. J Mol Recognit 18, 413-421

14.  Mirshahi, M., Shamsipour, F., Mirshahi, T., Khajeh, K., and Naderi-Manesh, H. (2006) A novel monoclonal antibody with catalytic activity against beta human chorionic gonadotropin. Immunol Lett 106, 57-62

15.  Planque, S., Taguchi, H., Burr, G., Bhatia, G., Karle, S., Zhou, Y. X., Nishiyama, Y., and Paul, S. (2003) Broadly distributed chemical reactivity of natural antibodies expressed in coordination with specific antigen binding activity. J Biol Chem 278, 20436-20443

16.  Polosukhina, D. I., Kanyshkova, T. G., Doronin, B. M., Tyshkevich, O. B., Buneva, V. N., Boiko, A. N., Gusev, E. I., Favorova, O. O., and Nevinsky, G. A. (2004) Hydrolysis of myelin basic protein by polyclonal catalytic IgGs from the sera of patients with multiple sclerosis. J Cell Mol Med 8, 359-368

17.  Lacroix-Desmazes, S., Bayry, J., Kaveri, S. V., Hayon-Sonsino, D., Thorenoor, N., Charpentier, J., Luyt, C. E., Mira, J. P., Nagaraja, V., Kazatchkine, M. D., Dhainaut, J. F., and Mallet, V. O. (2005) High levels of catalytic antibodies correlate with favorable outcome in sepsis. Proc Natl Acad Sci U S A 102, 4109-4113

18.  Ramsland, P. A., Terzyan, S. S., Cloud, G., Bourne, C. R., Farrugia, W., Tribbick, G., Geysen, H. M., Moomaw, C. R., Slaughter, C. A., and Edmundson, A. B. (2006) Crystal structure of a glycosylated Fab from an IgM cryoglobulin with properties of a natural proteolytic antibody. Biochem J 395, 473-481

19.  Okochi, N., Kato-Murai, M., Kadonosono, T., and Ueda, M. (2007) Design of a serine protease-like catalytic triad on an antibody light chain displayed on the yeast cell surface. Appl Microbiol Biotechnol 77, 597-603

20.  Ponomarenko, N. A., Pillet, D., Paon, M., Vorobiev, II, Smirnov, I. V., Adenier, H., Avalle, B., Kolesnikov, A. V., Kozyr, A. V., Thomas, D., Gabibov, A. G., and Friboulet, A. (2007) Anti-idiotypic antibody mimics proteolytic function of parent antigen. Biochemistry 46, 14598-14609

21.  Matsuura, K., Ohara, K., Munakata, H., Hifumi, E., and Uda, T. (2006) Pathogenicity of catalytic antibodies: catalytic activity of Bence Jones proteins from myeloma patients with renal impairment can elicit cytotoxic effects. Biol Chem 387, 543-548

22.  Rangan, S. K., Liu, R., Brune, D., Planque, S., Paul, S., and Sierks, M. R. (2003) Degradation of beta-amyloid by proteolytic antibody light chains. Biochemistry 42, 14328-14334

23.  Taguchi, H., Planque, S., Nishiyama, Y., Symersky, J., Boivin, S., Szabo, P., Friedland, R. P., Ramsland, P. A., Edmundson, A. B., Weksler, M. E., and Paul, S. (2008) Autoantibody-catalyzed hydrolysis of amyloid beta peptide. J Biol Chem 283, 4714-4722

24.  Taguchi, H., Planque, S., Sapparapu, G., Boivin, S., Hara, M., Nishiyama, Y., and Paul, S. (2008) Exceptional amyloid beta peptide hydrolyzing activity of nonphysiological immunoglobulin variable domain scaffolds. J Biol Chem 283, 36724-36733

25.  Goodglick, L., Zevit, N., Neshat, M. S., and Braun, J. (1995) Mapping the Ig superantigen-binding site of HIV-1 gp120. J Immunol 155, 5151-5159

26.  Karray, S., and Zouali, M. (1997) Identification of the B cell superantigen-binding site of HIV-1 gp120. Proc Natl Acad Sci U S A 94, 1356-1360

27.  Bermas, B. L., Petri, M., Berzofsky, J. A., Waisman, A., Shearer, G. M., and Mozes, E. (1994) Binding of glycoprotein 120 and peptides from the HIV-1 envelope by autoantibodies in mice with experimentally induced systemic lupus erythematosus and in patients with the disease. AIDS Res Hum Retroviruses 10, 1071-1077

28.  Karle, S., Planque, S., Nishiyama, Y., Taguchi, H., Zhou, Y. X., Salas, M., Lake, D., Thiagarajan, P., Arnett, F., Hanson, C. V., and Paul, S. (2004) Cross-clade HIV-1 neutralization by an antibody fragment from a lupus phage display library. AIDS 18, 329-331

29.  Paul, S., Karle, S., Planque, S., Taguchi, H., Salas, M., Nishiyama, Y., Handy, B., Hunter, R., Edmundson, A., and Hanson, C. (2004) Naturally occurring proteolytic antibodies: selective immunoglobulin M-catalyzed hydrolysis of HIV gp120. J Biol Chem 279, 39611-39619

30.  Planque, S., Mitsuda, Y., Taguchi, H., Salas, M., Morris, M. K., Nishiyama, Y., Kyle, R., Okhuysen, P., Escobar, M., Hunter, R., Sheppard, H. W., Hanson, C., and Paul, S. (2007) Characterization of gp120 Hydrolysis by IgA Antibodies from Humans without HIV Infection. AIDS Res Hum Retroviruses 23, 1541-1554

31.  Planque, S., Salas, M., Escobar, M., Morris, M. K., Jena, B., Mitsuda, Y., Sienczyk, M., Nishiyama Y, Kumar, A., Gao, F., Montefiori, D. C., Hanson, C. V., and Paul, S. Survivors of HIV infection produce potent, broadly neutralizing IgAs directed to the superantigenic region of the gp120 CD4 binding site. AIDS 2008, XVII International AIDS Conference, México City, México. 3-8 August, 2008.Abstract Number: THAA030

32.  Paul, S., Planque, S., Zhou, Y. X., Taguchi, H., Bhatia, G., Karle, S., Hanson, C., and Nishiyama, Y. (2003) Specific HIV gp120-cleaving antibodies induced by covalently reactive analog of gp120. J Biol Chem 278, 20429-20435

33.  Nishiyama, Y., Karle, S., Mitsuda, Y., Taguchi, H., Planque, S., Salas, M., Hanson, C., and Paul, S. (2006) Towards irreversible HIV inactivation: stable gp120 binding by nucleophilic antibodies. J Mol Recognit 19, 423-431

34.  Nishiyama, Y., Mitsuda, Y., Taguchi, H., Planque, S., Salas, M., Hanson, C. V., and Paul, S. (2007) Towards covalent vaccination: improved polyclonal HIV neutralizing antibody response induced by an electrophilic gp120 V3 peptide analog. J Biol Chem 282, 31250-31256

35.  Wirsching, P., Ashley, J. A., Lo, C. H., Janda, K. D., and Lerner, R. A. (1995) Reactive immunization. Science 270, 1775-1782

36.  Wagner, J., Lerner, R. A., and Barbas, C. F., 3rd (1995) Efficient aldolase catalytic antibodies that use the enamine mechanism of natural enzymes. Science 270, 1797-1800

37.  Nishiyama, Y., Planque, S., Mitsuda, Y., Nitti, G., Taguchi, H., Jin, L., Symersky, J., Boivin, S., Sienczyk, M., Salas, M., Hanson, C. V., and Paul, S. (2009) Towards effective HIV vaccination. Induction of Binary Epitope Reactive Antibodies with Broad HIV Neutralizing Activity. J Biol Chem

38.  Paul, S., Planque, S.A., Nishiyama, Y., and Hanson, C.V.  (2009) A covalent HIV vaccine: Is there hope for the future? Future Virology (Editorial) 4:7-10