Education

PhD
Biochemistry, The University of Texas Health Science Center at Houston, 2008
B.S.
Bioengineering, Université de Technologie de Compiègne, Compiegne, France, 1999

Areas of Interests

Research Interests

Chemically Reactive Antibodies

Research Information

My goals are to study the beneficial and harmful functional effects of antibodies using covalently reactive electrophilic analogs of antigens. The electrophilic antigen analogs provide a new way to a. inactivate autoantibodies by forming irreversible antibody-antigen adducts; and b. induce antibodies with covalent and catalytic character. Antibodies to autoantigens and foreign antigens mediate, respectively, various pathogenic and beneficial effects. I discovered that most if not all antibodies express naturally-occurring, enzyme-like nucleophiles that react covalently with electrophilic chemical probes. The reactivity of the probes with the antibody nucleophilic site is accelerated by traditional noncovalent binding, which brings the electrophilic and nucleophilic groups into proximity with each other. A subpopulation of nucleophilic Abs expresses proteolytic activity, which can inactivate the antigen molecule permanently. I want to determine how the nucleophilicity can be exploited to inhibit harmful antibodies against autoantigens and activate the synthesis of beneficial antibodies against microbes and pathogenic molecules.

Together with my collaborators, I have discovered the innate recognition of the HIV coat protein gp120 by IgM and IgA class antibodies isolated from humans and mice without HIV infection. These antibodies hydrolyzed gp120 by a nucleophilic mechanism and neutralized HIV-1 with modest potency by recognizing the gp120 421-433 epitope, a conserved B cell superantigenic region that is also essential for HIV-1 attachment to host cell CD4 receptors. Unlike conventional antigens that bind to antibody complementarity determining regions, the 421-433 epitope bind the framework regions of these antibodies. An adaptive immune response to B cell superantigens is generally prohibited, as this class of molecules downregulates B cells. I have observed that IgAs from subjects with very prolonged HIV-1 infection displayed improved catalytic hydrolysis of gp120 and exceptionally potent and broad neutralization of diverse CCR5-dependent primary HIV isolates attributable to recognition of the 421-433 epitope. This indicates slow immunological bypass of the superantigenic character of gp120, opening the path to effective HIV vaccination.

Dr Paul, Dr Nishiyama and I have engineered electrophilic derivatives of gp120 as prototype vaccines against HIV infection. Data accumulated in the past 15 years have indicated that electrophilic gp120 derivatives induce antibodies with covalent and catalytic activities. Both types of activity derive from adaptively enhanced nucleophilic reactivity of the antibodies. Covalent antibodies can bind the antigen irreversibly, and by this means, permanently inactivate it. Catalytic antibodies permanently alter the target antigen structure. Moreover, their turnover capability allows catalytic antibodies to inactivate multiple antigen molecules. Our group has hypothesized that covalent immunization induces antibodies capable of more efficient inactivation of microbes compared to traditional immunization. My studies also suggests the potential of electrophilic immunogens to induce a productive antibody response to superantigenic epitopes that are otherwise poor targets of adaptive immunity. I participate in and provide leadership in developing an effective HIV vaccine through our new approach in the next few years.

Catalytic antibodies can potentially be employed as immunotherapeutic reagents. Together with my collaborators, I am studying the feasibility of developing immunotherapeutic catalytic antibodies for HIV infection, Alzheimer disease and senile systemic amyloidosis.  I have isolated murine monoclonal antibodies after covalent immunization with electrophilic gp120 derivative. These monoclonal antibodies hydrolyze gp120 specifically and neutralize HIV potently. I have been awarded a phase I Small Business Technology Transfer grant application to develop these antibodies further. Similarly, I have isolated a catalytic anti-Ab(1-40) single chain antibody fragment from a phage-display library using electrophilic Ab(1-40) for selection. I continue providing leadership in the molecular and functional development of this antibody, including study of in vivo efficacy in clearing amyloid plaques in a U01 grant entitled “Efficacious and safe antibody catalyzed amyloid Beta clearance” for which I am a co-investigator. Finally, I am also a co-investigator in a small grant in which, I will try to isolate and characterize antibodies capable to specifically hydrolyze transthyretin aggregate, a hallmark of senile systemic amyloidosis that caused the death of supercentenarians.

I have demonstrated the inactivation of pathogenic Abs from Hemophilia A patients by means of nucleophile-electrophile pairing. Deficient factor VIII (FVIII) in HA subjects impairs blood coagulation. FVIII replacement therapy fails in 20-30% of HA patients due to production of anti-FVIII Abs. My approach consists of developing an electrophilic derivative of FVIII that can specifically and irreversibly inactivate the pathological anti-FVIII Abs. For evaluating in vivo efficacy, I intend to determine the pharmacokinetics of the electrophilic FVIII itself as well as its irreversible immune complex with antibodies in an animal model. In principle, development of electrophilic antigens for specific inactivation of autoantibodies could replace immunosuppressive drugs currently used for autoimmune disease treatment. The latter class of drugs induces a generalized inhibition of immune responses, and this leads to increased occurrence of infections. Inactivation of autoantibodies by electrophilic antigens, in contrast, holds the potential of neutralizing the specific subpopulation of antibodies with pathogenic effects without affecting the overall immune response.

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., et al. (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., et al. (2014) Physiological IgM class catalytic antibodies selective for transthyretin amyloid. Journal of Biological Chemistry. 289(19): 13243-13258.
  • Planque, S., Mitsuda, Y., Nishyama, Y., Sangeeta, K., Boivin, S., Salas, M., Morris, M., Hara, M., Liao, G., Massey, R., et al. (2012) Antibodies to a superantigenic glycoprotein 120 epitope as the basis for developing an HIV vaccine.  Journal of Immunology. 189(11): 5367-5381.
  • 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).
  • Sapparapu, G., Planque, S., Mitsuda, Y., McLean, G., Nishiyama, Y., and Paul, S. (2012) Constant domain-regulated antibody catalysis. J Biol Chem. 287(43):36096-104.
  • Paul, S., Planque, S.A., Nishiyama, Y., Hanson, C.V., and Massey, R.J. (2012) Nature and nurture of catalytic antibodies. Adv Exp Med Biol. 750:56-75.
  • 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. (2012) Constitutive production of catalytic antibodies to a Staphylococcus aureus virulence factor and effect of infection. J Biol Chem. 287(13):9940-51.
  • Paul, S., Planque, S., Nishiyama, Y., Escobar, M., Barnett, Z., and Massey, R.J. (2011) 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 2011:21-5.
  • Paul, S. and Planque, S. (2011) Antibody Engineering. Encyclopedia of Life Sciences. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net. DOI: 10.1002/9780470015902.a0001278.pub2.
  • Paul, S., Planque, S., Nishiyama, Y., Escobar, M.E., and Hanson, C.V. (2010) Back to the future: Covalent epitope-based HIV vaccine development. Expert Rev Vaccines. 9:1027-43.
  • Paul, S., Planque, S., and Nishiyama, Y. (2010) Immunological origin and functional properties of catalytic autoantibodies to amyloid β peptide. J Clin Immunol. 30 Suppl 1:S43-9.
  • 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. (2010) Neutralization of genetically diverse HIV-1 strains by IgA antibodies to the gp120 CD4 binding site from long-term survivors of HIV infection. AIDS. 24:875-84.
  • Paul, S., Planque, S., and Nishiyama, Y. (2010) Beneficial catalytic immunity to amyloid β peptide. Rejuvenation Res. 13:179-87.
  • 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. 284:30627-42.
  • Sapparapu, G., Planque, S., Nishiyama, Y., Foung, S.K., and Paul, S. (2009) Antigen-specific Proteolysis by Hybrid Antibodies Containing Promiscuous Proteolytic Light Chains Paired with an Antigen-binding Heavy Chain. J Biol Chem. 284:24622-33.
  • Paul, S., Planque, S., Nishiyama, Y., and Hanson, C.V. (2009) A covalent HIV vaccine: Is there hope for the future? Future Virology (Editorial) 4:7-10.

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.