Education

Fellowship
Alexander von Humboldt Fellow, University of Kiel, Department of Obstetrics and Gynecology, Kiel, West Germany, 1982
Ph.D.
Biochemistry, All-India Institute Medical Sciences, New Delhi, India, 1980
M.Sc.
Biochemistry, All-India Institute Medical Sciences, New Delhi, India, 1975
B.Sc. with Honors
Punjab University, Chandigarh, India, 1972

Areas of Interests

Research Interests

Development of Covalent Binding and Catalytic Activity in Antibodies

Research Information

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.

Publications

Publication Information

References

  • Planque, S. A., Nishiyama, Y., Sonoda, S., Lin, Y., Taguchi, H., Hara, M., Kolodziej, S., Mitsuda, Y., Gonzalez, V., Sait, H. B., Fukuchi, K., Massey, R. J., Friedland, R. P., O’Nuallain, B., Sigurdsson, E. M., and Paul, S. (2015) Specific amyloid beta clearance by a catalytic antibody construct. J Biol Chem 290, 10229-10241. PMCID: PMC4400338.
  • Paul, S., Planque, S. A., Massey, R.J. Antibody Engineering. In: Encyclopedia of Life Sciences, eLS. John Wiley & Sons Ltd, Chichester. 2015. DOI: 10.1002/9780470015902.a0001278.pub3.
  • Planque, S.A., Mitsuda, Y., Chitsazzadeh, V., Gorantla, S., Poluektova, L., Nishiyama, Y., Ochsenbauer, C., Morris, M., Sapparapu, G., Hanson, C.V., Massey, R.J., Paul, S. (2014) Deficient synthesis of class-switched, HIV-neutralizing antibodies to the CD4+ binding site and correction by electrophilic GP120 immunogen. AIDS. 28(15):2201-11.
  • Nishiyama, Y., Taguchi, H., Hara, M., Planque, S.A., Mitsuda, Y., Paul, S. (2014) Metal-dependent amyloid β-degrading catalytic antibody construct. Journal of Biotechnology. 180:17-22.
  • Kou, J., Yang, J., Lim, J., Pattanayak, A., Song, M., Planque, S., Paul, S., Fukuchi, K. (2014) Catalytic Immunoglobulin Gene Delivery in a Mouse Model of Alzheimer’s Disease: Prophylatic and Therapeutic Applications. Molecular Neurobiology.
  • Phay, M., Blinder, V., Macy, S., Greene, M.J., Wooliver, D.C., Liu, W., Planas, A., Walsh, D.M., Connors, L.H., Primmer, S.R., Planque, S.A., Paul, S., O’Nuallain, B. (2014) Transthyretin aggregate-specific antibodies recognize cryptic epitopes on patient-derived amyloid fibrils.  Rejuvenation Research.  17(2):97-104.
  • Planque, S.A., Nishiyama, Y., Hara, M., Sonoda, S., Murphy, S.K., Watanabe, K., Mitsuda, Y., Brown, E.L., Massey, R.J., Primmer, S.R., O’Nuallain, B., Paul, S. (2014) Physiological IgM class catalytic antibodies selective for transthyretin amyloid. Journal of Biological Chemistry. 289(19): 13243-13258.
  • 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

Additional Information

Patents
Pending, Treatment and diagnosis of transthyretin amyloidosis using catalytic antibodies. (2013) PCT Application PCT/US2014/047409. Sudhir Paul, Yasuhiro Nishiyama, Stephanie Planque.
Pending, Immunoglobulins directed to bacterial, viral and endogeneous polypeptides. (2009). ; U.S. Patent Publication US 12/589,440; Sudhir Paul, Stephanie Planque, Yasuhiro Nishiyama, Eric L. Brown, Keri C. Smith, Hiroaki Taguchi.
Pending, Binary epitope antibodies and B cell superantigen immune stimulants.  (2007) EPO Patent Publication EP2091973; Sudhir Paul, Yasuhiro Nishiyama, Stephanie Planque.
Pending, Catalytic Immunoglobulins and uses therefor. (2006) ; U.S. Application No US 11/988,761; Sudhir Paul, Yasuhiro Nishiyama, Carl V. Hanson, Marc Weksler.
Issued, Covalently reactive transition state analogs and methods of use thereof. (2005)  U.S. Patent No. 7,524,663; Sudhir Paul, Yasuhiro Nishiyama.
Issued, Covalently reactive transition state analogs and methods of use thereof.  (2005) U.S. Patent No. 6,855,804; Sudhir Paul, Yasuhiro Nishiyama.
Issued, Covalent attachment of ligands to nucleophilic proteins guided by non-covalent binding. (2005) Expiration date, 08/04/2028; U.S. Patent No 9,006,388; Sudhir Paul, Yasuhiro Nishiyama.
Issued, Methods for identifying inducers and inhibitors of proteolytic antibodies, compositions and their uses. (2005) Expiration date, 03/23/2018; U.S. Patent No. 6,855,528; Sudhir Paul, Gennady Gololobov, Larry J. Smith.
Issued, Lupus antibodies for passive immunotherapy of HIV/AIDS. (2004) Expiration date, 03/29/2026; U.S. Patent No 8,246,957; Sudhir Paul. License information, Covalent Bioscience is the owner.
Issued, Proteolytic and covalent antibodies. (2004) Expiration date, 08/04/2028; U.S. Patent No 8,980,646; Sudhir Paul, Yasuhiro Nishiyama.
Issued, Compositions and methods for catalyzing hydrolysis of HIV gp120. (2000) Expiration date, 07/19/2016; U.S. Patent No. 6,156,541; Sudhir Paul, Ravishankar Kalaga.
Pending, Combined chemotherapy compositions and methods for the treatment of cancer, ischemia-reperfusion injury, and septic shock. (2005) U.S. Patent Publication 20050214295; Sudhir Paul, Gennady Gololobov, Larry J. Smith.
Issued, Methods for identifying inducers and inhibitors of proteolytic antibodies, compositions and their uses. (2001) U.S. Patent No. 6,235,714; Sudhir Paul, Gennady Gololobov, Larry J. Smith.
Issued, Assay methods and kits for diagnosing autoimmune disease. (2000) U.S. Patent No. 6,130,049; Sudhir Paul, Ravishankar Kalaga.
Issued, Inhibitors of catalytic antibodies. (2000) U.S. Patent No. 6,048,717; Sudhir Paul, Michael J. Powell, Richard J. Massey.
Issued, Method of delivering a vasoactive intestinal polypeptide, an encapsulated vasoactive intestinal polypeptide, and a method of making the encapsulated vasoactive intestinal polypeptide. (1998) U.S. Patent No. 5,770,570; Sudhir Paul, Yasuko Noda, Israel Rubinstein.
Issued, Catalytic antibody components. (1997) U.S. Patent No. 5,658,753; Sudhir Paul, Michael J. Powell, Richard J. Massey, John H. Kenten.
Issued, Autoantibodies which enhance the rate of a chemical reaction. (1997) U.S. Patent No. 5,602,015; Sudhir Paul.
Issued, Autoantibodies which enhance the rate of a chemical reaction. (1997) U.S. Patent No. 5,599,538; Sudhir Paul, Lan Li, Srini Kaveri.
Issued, Monoclonal antibody and antibody components elicited to a polypeptide antigen ground state. (1994) U.S. Patent No. 5,318,897; Sudhir Paul.
Issued, Autoantibodies which enhance the rate of a chemical reaction. (1993) U.S. Patent No. 5,236,836; Sudhir Paul.
Issued, Catalytic antibody components. (1993) U.S. Patent No. 5,229,272; Sudhir Paul, Michael J. Powell, Richard J. Massey, John H. Kenten.
Issued, Inhibitors of catalytic antibodies. (1993) U.S. Patent No. 5,194,585; Sudhir Paul, Michael J. Powell, Richard J. Massey.