References:
- Nishiyama, Y., Planque, S., Hanson, C.V., Massey, R.J., and Paul, S. CD4 binding determinant mimicry for HIV vaccine design. Frontiers in Immunology. In revision, 2012 (Invited article).
- Planque, S.A., Mitsuda, Y., Nishiyama, Y., Karle, S., Boivin, S., Salas, M., Morris, M.-K., Hara, M., Liao, G., Massey, R.J., Hanson, C.V., and Paul, S. Antibodies to a superantigenic glycoprotein 120 epitope as the basis for developing a HIV vaccine. J Immunol. 2012 Oct 22. [Epub ahead of print]. Pubmed
- Yang, J., Pattanayak, A., Song, M., Kou, J., Taguchi, H., Paul, S., Ponnazhagan, S., Lalonde, R., and Fukuchi, KI. Muscle-directed anti-Aβ single-chain antibody delivery via AAV1 reduces cerebral Aβ load in an Alzheimer's disease mouse model. J Mol Neurosci. 2012 Sep 4. [Epub ahead of print]. Pubmed
- Sapparapu, G., Planque, S., Mitsuda, Y., McLean, G., Nishiyama, Y., and Paul, S. Constant domain-regulated antibody catalysis. J Biol Chem. 287(43):36096-36104, 2012. Pubmed
- Paul, S., Planque, S.A., Nishiyama, Y., Hanson, C.V., and Massey, R.J. Nature and nurture of catalytic antibodies. Adv Exp Med Biol. 750:56-75, 2012. Pubmed
- Brown, E.L., Nishiyama, Y., Dunkle, J.W., Aggarwal, S., Planque, S., Watanabe, K., Csencsits-Smith, K., Bowden, M.G., Kaplan, S.L., and Paul, S. Constitutive production of catalytic antibodies to a Staphylococcus aureus virulence factor and effect of infection. J Biol Chem. 287(13):9940-9951, 2012. Pubmed
- Nishiyama, Y. and Paul, S. VIPase: antibody light chain hydrolyzing vasoactive intestinal peptide. Handbook of Proteolytic Enzymes. 3rd Edition, Rawlings, N.D. and Salvesen, G., Eds. (Academic Press, London, England). Expected Release Date 2013 Jan 17.
- Kou, J., Kim, H., Pattanayak, A., Song, M., Lim, J.E., Taguchi, H., Paul, S., Cirrito, J.R., Ponnazhagan, S., and Fukuchi, K. Anti-amyloid-β single-chain antibody brain delivery via AAV reduces amyloid load but may increase cerebral hemorrhages in an Alzheimer's disease mouse model. J Alzheimers Dis. 27(1):23-38, 2011. Pubmed
- Paul, S., Planque, S., Nishiyama, Y., Escobar, M., Barnett, Z., and Massey, R.J. Covalent vaccination and catalytic antibodies: A new way of looking at and dealing with HIV. GMHC “Treatment Issues.” June 2011. Print version published in POZ magazine, June 2011:21-25. GMHC Link
- Paul, S. and Planque, S. Antibody Engineering. Encyclopedia of Life Sciences. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net. DOI: 10.1002/9780470015902.a0001278.pub2. 2011.
- Paul, S. Two-faced catalytic autoantibodies (Commentary). Blood. 117(7):2084-2086, 2011.
- 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. Rejuvenation Res. 13:179-187, 2010. 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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