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  1. Science & Research (Biologics)

Evaluation and Characterization of Neutralizing Antibodies against Viruses Relevant to Blood-derived Products

 

Pei Zhang, MD. Headshot

Pei Zhang, MD

Office of Tissues and Advanced Therapies
Division of Plasma Protein Therapeutics
Plasma Derivatives Branch

Pei.Zhang@fda.hhs.gov


Biosketch

Dr. Pei Zhang graduated from Peking Union Medical College and Chinese Academy of Medical Sciences in Beijing, China. He did post-doctoral training on T-cell signaling transduction and transcription regulation of hepatitis B virus at the Scripps Research Institute in California. He is now a principal investigator at CBER/FDA, where he works primarily on clarifying the molecular and structural basis for antibody-mediated neutralization of hepatitis C virus and other emerging viruses, such as Zika, Ebola, and SARS.  Dr. Zhang has more than 20 scientific publications on these topics in major peer-reviewed journals.


General Overview

Protein is hardly a static object, instead, it is an ensemble of populated conformational states. The dynamics of these conformations, operating often in a variety of space and time scales, govern the different functions of the protein. In the case of the hepatitis C virus, the envelope glycoprotein E2, as a major target for neutralizing antibodies, is anticipated to be flexible, even though its core structure appears to be well-maintained by intramolecular chemical bonds. One of the consequences of such structural flexibility is the increased probability of the virus deterring the host immune system from generating site-specific antibodies to effectively neutralize the virus. Through various biochemical and biophysical approaches, our research has been focused on the characterization of the dynamic process of the E2 structure and the underlying mechanism of antibody-mediated neutralization. These studies will not only help us understand the basis for HCV neutralization, but also develop appropriate assays for evaluating the potency of FDA-regulated “specific immune globulin” products. 


Scientific Overview

Our research program addresses the antibody-mediated neutralization of hepatitis C and other emerging viruses such as Zika. We continue to characterize the molecular and structural features that connect to the neutralizing antibody activities. The information provided by our studies will contribute broadly to the prevention and treatment of viral diseases. This research program is considered to be relevant to FDA's mission, since it focuses on a major public health problem, and is an unmet need for the improvement of FDA-regulated immune globulin products.

The envelope glycoprotein E2 is the most promising target for antibody neutralization because it plays an essential role in binding to the host entry factor CD81.  Structurally, E2 is very flexible.  The flexibility of E2 not only affects the optimal presentation of the immunogenic sites of interest, but also renders immune evasion for HCV. 

Two major aspects are thus addressed in our studies: 1) Is the conformational state of HCV E2 connected with the outcome of antibody-mediated neutralization or non-neutralization? and 2) Is the physic-chemical characteristic of the antibody connected with its neutralizing ability? Through a series of biochemical, computational and X-ray crystallographic analyses, we have demonstrated that the HCV E2 epitope can adopt at least two interchangeable conformations. The epitope simply rearranges its residues, without altering the amino acid sequence, to create distinctive interfaces in the context of the E2 protein structure for binding to CD81 or site-specific antibodies. Our study thus supports that the alternation between these conformational states of the epitope may play a part in orchestrating antibody-mediated neutralization and CD81-mediated infection of HCV. The structural heterogeneity found in the HCV E2 may reflect the situation when antibodies are elicited during the natural course of HCV infection, thereby leading to disease resolution or persistent infection.

Through comparative analyses of X-ray crystal structures of non-neutralizing and neutralizing antibodies bound to a linear HCV E2 "neutralization epitope", we have also uncovered two distinct modes of action. Depending on how the intramolecular bonding network is formed within the antibody molecules, the antibody's neutralizing capacity will be governed by selecting the mode of actions of "lock and key" or "induced fit". These observations allow us, from the point of view of an antibody, to reveal an antibody neutralization mechanism operating at a single epitope site. 

Together, our studies suggest that the host immune cells may produce antibodies with different neutralizing qualities depending on which conformation of the epitope happens to present on the HCV to the host immune system at the time of infection. These structural insights into the capacity of antibody to disrupt E2 structural transition will allow us to identify the vulnerability in HCV that forms the basis of antibody intervention.


Important Links


Publications

  1. Viruses 2023 Oct 31;15(11):2190
    Nanoluciferase reporter Zika viruses as tools for assessing infection kinetics and antibody potency.
    Xu Y, Vertrees D, He Y, Momben-Abolfath S, Li X, Brewah YA, Scott DE, Konduru K, Rios M, Struble EB
  2. J Infect Dis 2023 Sep 5 [Epub ahead of print]
    Report of the Assay Guidance Workshop on 3-Dimensional Tissue Models for Antiviral Drug Development.
    Jordan R, Ford-Scheimer SL, Alarcon RM, Atala A, Borenstein JT, Brimacombe KR, Cherry S, Clevers H, Davis MI, Funnell SGP, Gehrke L, Griffith LG, Grossman AC, Hartung T, Ingber DE, Kleinstreuer NC, Kuo CJ, Lee EM, Mummery CL, Pickett TE, Ramani S, Rosado-Olivieri EA, Struble EB, Wan Z, Williams MS, Hall MD, Ferrer M, Markossian S
  3. Vaccines 2022 Nov 30;10(12):2059
    Zika virus infection and antibody neutralization in FcRn expressing placenta and engineered cell lines.
    Xu Y, He Y, Momben-Abolfath S, Vertrees D, Li X, Norton MG, Struble EB
  4. J Clin Pharmacol 2022 Sep;62(Suppl. 1):S36-52
    Prenatal somatic cell gene therapies: charting a path toward clinical applications (proceedings of the CERSI-FDA meeting).
    Herzeg A, Almeida-Porada G, Charo RA, David AL, Gonzalez-Velez J, Gupta N, Lapteva L, Lianoglou B, Peranteau W, Porada C, Sanders SJ, Sparks TN, Stitelman DH, Struble E, Sumner CJ, MacKenzie TC
  5. J Med Virol 2022 Feb;94(2):649-58
    Multiple epitopes of hepatitis B virus surface antigen targeted by human plasma-derived immunoglobulins coincide with clinically observed escape mutations.
    Tarafdar S, Virata ML, Yan H, Zhong L, Deng L, Xu Y, He Y, Struble E, Zhang P
  6. Proc Natl Acad Sci U S A 2021 Jul 13;118(28):e2104242118
    A conserved epitope III on hepatitis C virus E2 protein has alternate conformations facilitating cell binding or virus neutralization.
    Deng L, Hernandez N, Zhong L, Holcomb DD, Yan H, Virata ML, Tarafdar S, Xu Y, He Y, Struble E, Alter HJ, Zhang P
  7. Vaccines 2021 Feb 11;9(2):145
    Entry and disposition of Zika virus immune complexes in a tissue culture model of the maternal-fetal interface.
    Xu Y, He Y, Momben-Abolfath S, Eller N, Norton M, Zhang P, Scott D, Struble EB
  8. J Immunol Res 2017;2017:7373196
    Passive immunoprophylaxis for the protection of the mother and her baby: insights from in vivo models of antibody transport.
    Xu Y, Mahmood I, Zhong L, Zhang P, Struble EB
  9. Hepatology 2015 Dec;62(6):1670-82
    Antibodies to an interfering epitope in hepatitis C Virus E2 can mask vaccine-induced neutralizing activity.
    Kachko A, Frey SE, Sirota L, Ray R, Wells F, Zubkova I, Zhang P, Major ME
  10. Placenta 2015 Dec;36(12):1370-7
    Gestation age dependent transfer of human immunoglobulins across placenta in timed-pregnant guinea pigs.
    Xu Y, Ma L, Norton MG, Stuart C, Zhao Z, Toibero D, Dahlen S, Zhong L, Zhang P, Struble EB
  11. J Virol 2015 Jan;89(1):492-501
    A view of the E2-CD81 interface at the binding site of a neutralizing antibody against hepatitis C virus.
    Harman C, Zhong L, Ma L, Liu P, Deng L, Zhao Z, Yan H, Struble E, Virata-Theimer ML, Zhang P

 

 
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