References:
- Paul, S., Planque, S., Nishiyama, Y., Escobar, M.E., and Hanson, C.V. Back to the future: Covalent epitope-based HIV vaccine development. Expert Rev Vaccines. 9:1027-1043, 2010. Pubmed
- Paul, S., Planque, S., and Nishiyama, Y. Immunological origin and functional properties of catalytic autoantibodies to amyloid β peptide. J Clin Immunol. 30 Suppl 1:S43-S49, 2010. Pubmed
- Planque, S., Salas, M., Mitsuda, Y., Sienczyk, M., Escobar, M.E., Mooney, J.P., Morris, M.-K., Nishiyama, Y., Ghosh, D., Kumar, A., Gao, F., Hanson, C.V., and Paul, S. Neutralization of genetically diverse HIV-1 strains by IgA antibodies to the gp120 CD4 binding site from long-term survivors of HIV infection. AIDS. 24:875-884, 2010. Pubmed
- Paul, S., Planque, S., and Nishiyama, Y. Beneficial catalytic immunity to amyloid β peptide. Proceedings of the Fourth Conference of Strategies for Engineered Negligible Senescence (SENS4). September 3-7, 2009. Queens’ College, Cambridge, United Kingdom. Rejuvenation Res. 13:179-187, 2010. Pubmed
- 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. Towards effective HIV vaccination: Induction of binary epitope reactive antibodies with broad HIV neutralizing activity. J Biol Chem. 284:30627-30642, 2009. Pubmed
- Sapparapu, G., Planque, S.A., Nishiyama, Y., Foung, S.K., and Paul, S. Antigen-specific proteolysis by hybrid antibodies containing promiscuous proteolytic light chains paired with an antigen-binding heavy chain. J Biol Chem. 284:24622-24633, 2009. Pubmed
- Paul, S., Planque, S.A., Nishiyama, Y., and Hanson, C.V. A covalent HIV vaccine: Is there hope for the future? Future Virology (Editorial) 4:7-10, 2009. Article.
- Taguchi, H., Planque, S., Nishiyama, Y., Symersky, J., Boivin, S., Szabo, P., Friedland, R.P., Ramsland, P.A., Edmundson, A.B., Weksler, M.E., Paul, S. Autoantibody catalyzed hydrolysis of amyloid β peptide. J. Biol. Chem. 283:4714-4722, 2008. Pubmed.
- 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., Paul, S. Characterization of gp120 hydrolysis by IgA antibodies from humans without HIV infection. AIDS Research and Human Retroviruses. 23:1541-1553, 2007. Pubmed.
- Nishiyama, Y., Mitsuda, Y., Taguchi, H., Planque, S., Salas, M., Hanson, C.V., and Paul, S. Towards covalent vaccination: Improved polyclonal HIV neutralizing antibody response induced by an electrophilic gp120 V3 peptide analog. J. Biol. Chem. 282:31250-31256, 2007. Pubmed
- Mitsuda, Y., Planque, S., Hara, M., Kyle, R., Taguchi, H., Nishiyama, Y., and Paul, S. Naturally occurring catalytic antibodies: Evidence for preferred development of the catalytic function in IgA class antibodies. Mol. Biotechnol. 36:113-122, 2007. Pubmed.
- Nishiyama, Y., Karle, S., Planque, S., Taguchi, H., Paul, S. Antibodies to the superantigenic Site of HIV-1 gp120: Hydrolytic and binding activities of the light chain subunit. Mol. Immunol. 44:2707-2718, 2007. Pubmed.
- Nishiyama, Y., Karle, S., Mitsuda, Y., Taguchi, H., Planque, S., Salas, M., Hanson, C., and Paul, S. Towards irreversible HIV inactivation: stable gp120 binding by nucleophilic antibodies. J. Mol. Recognit. 19:423-431, 2006. Pubmed.
- Paul, S., and Planque, S. (2006) Antibody engineering. In: Nature Encyclopedia of Life Sciences, London: Nature Publishing Group, John Wiley & Sons, Ltd: Chichester http://www.els.net/ [DOI: 10.1038/npg.els.0001278], Published online: January 27, 2006.
- Paul, S., Nishiyama, Y., Planque, S., and Taguchi, H. Theory of proteolytic antibody occurrence. Immunol. Lett. 103:8-16, 2006. Pubmed
Sudhir Paul, PhD
Professor
Director,
Chemical Immunology Research Center
Pathology & Laboratory Medicine
(713) 500 - 5347
Sudhir.Paul@uth.tmc.edu
Development of Covalent Binding and Catalytic Activity in Antibodies
RESEARCH CONTRIBUTIONS
Key terms:
- Basic immunology and chemistry of covalent antibodies/catalytic antibodies
- Protein nucleophilicity and electrophilicity
- Therapeutic catalytic antibodies to neuropeptides, amyloids, HIV, HCV and Staph aureus
- Covalent vaccination against intractable microbes
- Superantigens
- B cell tolerance
We discovered antibodies that catalyze the cleavage of polypeptides. Proteolytic antibodies inactivate the target antigen permanently and a single antibody molecule is reused to cleave thousands of antigen molecules. We isolate high turnover, specific proteolytic antibodies from libraries for passive immunotherapeutic applications and we induce synthesis of the antibodies against intractable diseases. Structural and kinetic methods are applied to learn how coordinated noncovalent binding and nucleophilic attack results in specific antibody catalysis of defined targets. The antibodies bond the target polypeptide covalently via nucleophile-electrophile pairing. If the active site contains a properly oriented water molecule, the reaction proceeds to peptide bond hydrolysis. Based on the reaction mechanism, we engineer electrophilic antigen analogs that induce proteolytic antibodies by recruitment of the innate nucleophilic antibody repertoire and adaptive improvement of the antibody combining site.
We focus on targeting harmful proteins, both toxic endogenous proteins and proteins used by microbes. Our translational studies concern removal of amyloid plaques in Alzheimer’s disease and removal of proteins used by HIV, HCV and Staphylococcus aureus. Targeting cancer-associated antigens is also feasible. Lead proteolytic antibodies to amyloid-beta and HIV suitable for clinical development have been developed.
Injection of the proteolytic anti-amyloid beta antibody into the brain clears amyloid plaques in a mouse model. The next task is to remove amyloid plaques and improve cognition without unacceptable toxicity by systemic administration of the proteolytic antibody.
The difficulty in HIV immunotherapy derives from the diversity of envelope structures expressed by HIV strains across the world. We isolated a rare antibody to a conserved HIV gp120 region that neutralizes genetically divergent HIV strains with exceptional potency. The antibody is suitable for development as an HIV therapy, in particular, for patients resistant to protease inhibitor/reverse transcriptase inhibitor drugs.
Eradication of HIV will require a prophylactic vaccine. We have a synthetic electrophilic analog of HIV gp120 with the unique capability of inducing proteolytic antibodies to the Achilles heel of HIV, the CD4 binding site of gp120. This is the first vaccine candidate that induces neutralizing antibodies to genetically divergent HIV strains.
Our HIV vaccine studies have yielded a serendipitous discovery. Covalent B cell stimulation bypasses the immunosuppressive effect of microbial superantigens and induces a protective antibody response. We plan to test this principle for development of effective vaccines to other intractable infections, e.g., Staphylococcus aureus, a bacterium producing abundant virulence factors with superantigenic character.
Electrophilic antigen analogs may also be useful in dealing with the opposite problem of pathogenic autoantibodies in autoimmune disease and patients receiving therapeutic proteins (e.g., hemophilia A patients receiving Factor VIII). Covalent antibody inactivation may relieve antibody pathogenic effects permanently, exemplified by our report of an electrophilic Factor VIII analog (E-FVIII) that provides irreversible relief from inhibition of blood coagulation by anti-FVIII antibodies. Massive FVIII doses can induce immune tolerance in hemophilia A patients, but the procedure is only partially effective and it is expensive. E-FVIII was more potent than FVIII in suppressing the production of anti-FVIII antibodies by memory B cells in culture, suggesting the potential of more effective immune tolerance using the covalently binding electrophilic antigen analogs.
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