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Planque S.A.,University of Houston | Mitsuda Y.,University of Houston | Chitsazzadeh V.,University of Houston | Gorantla S.,University of Nebraska Medical Center | And 8 more authors.
AIDS | Year: 2014

Objective: HIV is vulnerable to antibodies that recognize a linear CD4 binding site epitope of gp120 (CLIN), but inducing CLIN-directed antibody synthesis by traditional vaccine principles is difficult. We wished to understand the basis for deficient CLIN- directed antibody synthesis and validate correction of the deficiency by an electrophilic gp120 analog (E-gp120) immunogen that binds B-cell receptors covalently. Methods: Serum antibody responses to a CLIN peptide and full-length gp120 epitopes induced by HIV infection in humans and immunization of mice with gp120 or E-gp120 were monitored. HIV neutralization by monoclonal and variable domain-swapped antibodies was determined from tissue culture and humanized mouse infection assays. Results: We describe deficient CLIN-directed IgG but not IgMantibodies in HIV-infected patients and mice immunized with gp120 accompanied by robust synthesis of IgGs to the immunodominant gp120 epitopes. Immunization with the E-gp120 corrected the deficient CLIN-directed IgG synthesis without overall increased immunogenicity of the CLIN or other gp120 epitopes. E-gp120-induced monoclonal IgGs neutralized diverse HIV strains heterologous to the immunogen. A CLIN-directed IgG neutralized HIV more potently compared to its larger IgM counterpart containing the same variable domains, suggesting obstructed access to HIV surface-expressed CLIN. An E-gp120-induced IgG suppressed HIV infection in humanized mice, validating the tissue culture neutralizing activity. Conclusion: A CLIN-selective physiological defect of IgM→IgG class-switch recombination (CSR) or restricted post-CSR B-cell development limits the functional utility of the humoral immune response to gp120. The E-gp120 immunogen is useful to bypass the restriction and induce broadly neutralizing CLIN-directed IgGs (see Supplemental Video. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Planque S.A.,University of Houston | Nishiyama Y.,University of Houston | Sonoda S.,University of Houston | Lin Y.,New York University | And 13 more authors.
Journal of Biological Chemistry | Year: 2015

Classical immunization methods do not generate catalytic antibodies (catabodies), but recent findings suggest that the innate antibody repertoire is a rich catabody source. We describe the specificity and amyloid β (Aβ)-clearing effect of a catabody construct engineered from innate immunity principles. The catabody recognized the Aβ C terminus noncovalently and hydrolyzed Aβ rapidly, with no reactivity to the Aβ precursor protein, transthyretin amyloid aggregates, or irrelevant proteins containing the catabody-sensitive Aβ dipeptide unit. The catabody dissolved preformed Aβ aggregates and inhibited Aβaggregation more potently than an Aβ-binding IgG. Intravenous catabody treatment reduced brain Aβ deposits in a mouse Alzheimer disease model without inducing microgliosis or microhemorrhages. Specific Aβ hydrolysis appears to be an innate immune function that could be applied for therapeutic Aβ removal. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.


PubMed | Illinois College, New York University, University of Louisville, Covalent Bioscience, Inc. and 2 more.
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2015

Classical immunization methods do not generate catalytic antibodies (catabodies), but recent findings suggest that the innate antibody repertoire is a rich catabody source. We describe the specificity and amyloid (A)-clearing effect of a catabody construct engineered from innate immunity principles. The catabody recognized the A C terminus noncovalently and hydrolyzed A rapidly, with no reactivity to the A precursor protein, transthyretin amyloid aggregates, or irrelevant proteins containing the catabody-sensitive A dipeptide unit. The catabody dissolved preformed A aggregates and inhibited A aggregation more potently than an A-binding IgG. Intravenous catabody treatment reduced brain A deposits in a mouse Alzheimer disease model without inducing microgliosis or microhemorrhages. Specific A hydrolysis appears to be an innate immune function that could be applied for therapeutic A removal.


Paul S.,University of Houston | Paul S.,Covalent Bioscience, Inc. | Planque S.A.,University of Houston | Nishiyama Y.,University of Houston | And 2 more authors.
Advances in Experimental Medicine and Biology | Year: 2012

Immunoglobulins (antibodies) frequently express constitutive functions. Two such functions are nucleophilic catalysis and the reversible binding to B-cell superantigens. Constitutive or naturally-occurring antibodies are produced spontaneously from germline genetic information. The antibody structural elements mediating the constitutive functions have originated over millions of years of phylogenic evolution, contrasting with antigen-driven, somatic sequence diversification of the complementarity determining regions (CDR) that underlies the better-known high affinity antigen binding function of antibodies. Often, the framework regions (FRs) play a dominant role in antibody constitutive functions. Catalytic antibody subsets with promiscuous, autoantigen-directed and microbe-directed specificities have been identified. Mucosal antibodies may be specialized to express high-level catalytic activity against microbes transmitted by the mucosal route, exemplified by constitutive production of IgA class antibodies in mucosal secretions that catalyze the cleavage of HIV gp120. Catalytic specificity can be gained by constitutive noncovalent superantigen binding at the FRs and by adaptive development of noncovalent classical antigen or superantigen binding, respectively, at the CDRs and FRs. Growing evidence suggests important functional roles for catalytic antibodies in homeostasis, autoimmune disease and protection against infection. Adaptive antibody responses to microbial superantigens are proscribed underphysiological circumstances. Covalent electrophilic immunogen binding to constitutively expressed nucleophilic sites in B-cell receptors bypasses the restriction on adaptive antibody production, and simultaneous occupancy of the CDR binding site by a stimulatory antigenic epitope can also overcome the downregulatory effect of superantigen binding at the FRs. These concepts may be useful for developing novel vaccines that capitalize and improve on constitutive antibody functions for protection against microbes. © 2012 Landes Bioscience and Springer Science+Business Media, LLC.


Nishiyama Y.,University of Houston | Planque S.,University of Houston | Hanson C.V.,Viral and Rickettsial Disease Laboratory | Massey R.J.,Covalent Bioscience, Inc. | Paul S.,University of Houston
Frontiers in Immunology | Year: 2012

The immunodominant epitopes expressed by the HIV-1 envelope protein gp120 are hypermutable, defeating attempts to develop an effective HIV vaccine. Targeting the structurally conserved gp120 determinant that binds host CD4 receptors (CD4BD) and initiates infection is a more promising route to vaccination, but this has proved difficult because of the conformational flexibility of gp120 and immune evasion mechanisms used by the virus. Mimicking the outer CD4BD conformational epitopes is difficult because of their discontinuous nature. The CD4BD region composed of residues 421-433 (CD4BDcore) is a linear epitope, but this region possesses B cell superantigenic character. While superantigen epitopes are vulnerable to a small subset of spontaneously produced neutralizing antibodies present in humans without infection (innate antibodies), their non-covalent binding to B cell receptors (BCRs) does not stimulate an effective adaptive response from B cells. Covalent binding at naturally occurring nucleophilic sites of the BCRs by an electrophilic gp120 (E-gp120) analog is a promising solution. E-gp120 induces the synthesis of neutralizing antibodies the CD4BDcore. The highly energetic covalent reaction is hypothesized to convert the abortive superantigens-BCR interaction into a stimulatory signal, and the binding of a spatially distinct epitope at the traditional combining site of the BCRs may furnish a second stimulatory signal. Flexible synthetic peptides can detect pre-existing CD4BDcore-specific neutralizing antibodies. However, induced-fit conformational transitions of the peptides dictated by the antibody combining site structure may induce the synthesis of non-neutralizing antibodies. Successful vaccine targeting of the CD4BD will require a sufficiently rigid immunogen that mimics the native epitope conformation and bypasses B cell checkpoints restricting synthesis of the neutralizing antibodies. © 2012 Nishiyama, Planque, Hanson, Massey and Paul.


Planque S.A.,University of Houston | Nishiyama Y.,University of Houston | Hara M.,University of Houston | Sonoda S.,University of Houston | And 8 more authors.
Journal of Biological Chemistry | Year: 2014

Peptide bond-hydrolyzing catalytic antibodies (catabodies) could degrade toxic proteins, but acquired immunity principles have not provided evidence for beneficial catabodies. Transthyretin (TTR) forms misfolded β-sheet aggregates responsible for age-Associated amyloidosis. We describe nucleophilic catabodies from healthy humans without amyloidosis that degraded misfolded TTR (misTTR) without reactivity to the physiological tetramericTTR(phyTTR). IgM classBcell receptors specifically recognized the electrophilic analog of misTTR but not phyTTR. IgM but not IgG class antibodies hydrolyzed the particulate and soluble misTTR species. No misTTR-IgM binding was detected. The IgMs accounted for essentially all of the misTTR hydrolytic activity of unfractionated human serum. The IgMs did not degrade non-Amyloidogenic, non-superantigenic proteins. Individual monoclonal IgMs (mIgMs) expressed variable misTTR hydrolytic rates and differing oligoreactivity directed to amyloid β peptide and microbial superantigen proteins. A subset of the mIgMs was monoreactive for misTTR. Excess misTTR was dissolved by a hydrolytic mIgM. The studies reveal a novel antibody property, the innate ability of IgMs to selectively degrade and dissolve toxic misTTR species as a first line immune function. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 600.00K | Year: 2011

DESCRIPTION (provided by applicant): We propose a Phase I STTR study to develop a novel human immunodeficiency virus (HIV) vaccine strategy with the potential of world-wide efficacy. The HIV/AIDS pandemic remains a major global burden. No test vaccine based on traditional scientific principles has induced sufficiently protective immunity to HIV. Induction of neutralizing antibodies (Abs), the cornerstone of vaccination against microbes, has been thwarted by: (a) mutability of the immunodominant viral epitopes, and (b) poor adaptive immunological response to conserved epitopes important in virus-host cell interactions. CD4 binding by the HIV envelope glycoprotein gp120 is an obligatory step in the HIV life cycle. gp120 residues 421-433 constitute the mostly-conserved core of the CD4 binding site (CD4BScore). Except for rare survivors of prolonged HIV infection, the immune system does not support the production of anti-CD4BScore Abs. The proposed Phase I project focuses on electrophilic immunogens (E-immunogens) derived from the novel chemical engineering strategy termed Covalent Vaccination concept. E-immunogens hold the potential of inducing the synthesis of protective Abs that is beyond the scope of the physiological immune response. We will carry out the following developmental studies: (i) Characterize and compare the protective anti-HIV properties of rabbit and mouse antibodies raised by immunization with electrophilic derivatives of purified gp120 and synthetic 416-433 peptide; (ii) Maximize the antibody response to the lead E-immunogen using alternate adjuvants. Proving preclinical proof-of-principle for covalent vaccination as an effective approach in the present project is an important step in translating this approach for HIV vaccination.PUBLIC HEALTH RELEVANCE: This project is directed toward developing a novel vaccine strategy for HIV infection. If the strategy is proven valid, the project holds the potential of contributing a candidate HIV vaccine suitable for advanced preclinical studies and commercial development.

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