Crystal structure of an idiotype-anti-idiotype Fabcomplex.

Ban, Nenad; Escobar, Carlos; Garcia, R. Guevara; Hasel, Karl W.; Day, John; Greenwood, Aaron; McPherson, Alexander

doi:10.1073/pnas.91.5.1604

Cited by 99 publications

(51 citation statements)

References 27 publications

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“…S3) are tightly engaged with each other, burying a total surface area of 1,460 Å 2 upon complex formation. This value is within the range (1,231 to 1,750 Å 2 ) observed for comparable idiotype-anti-idiotype complexes reported previously (7)(8)(9)(10). Their respective H3 CDRs are located approximately at the center of the interface, but the variable dimers are rotated by ϳ90°along the long axis of the complex with respect to each other, such that the contribution of V H of HM14c10 to the interaction with E1 (interface of 730 Å 2 ) significantly exceeds the involvement of its V L region (interface of 197 Å 2 ) …”

Section: Resultssupporting

confidence: 63%

Structural Mimicry of the Dengue Virus Envelope Glycoprotein Revealed by the Crystallographic Study of an Idiotype–Anti-idiotype Fab Complex

Wong

Goh

Lim

et al. 2017

J Virol

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A detailed understanding of the fine specificity of serotype-specific human antibodies is vital for the development and evaluation of new vaccines for pathogenic flaviviruses such as dengue virus (DENV) and Zika virus. In this study, we thoroughly characterize the structural footprint of an anti-idiotype antibody (E1) specific for a potent, fully human DENV serotype 1-specific antibody, termed HM14c10, derived from a recovered patient. The crystal structure at a resolution of 2.5 Å of a complex between the Fab fragments of E1 and HM14c10 provides the first detailed molecular comparison of an anti-idiotype paratope specific for a human antibody with its analogous epitope, a discontinuous quaternary structure located at the surface of the viral particle that spans adjacent envelope (E) proteins. This comparison reveals that the footprints left by E1 and E on HM14c10 largely overlap, explaining why the formation of binary complexes is mutually exclusive. Structural mimicry of the DENV E epitope by the E1 combining site is achieved via the formation of numerous interactions with heavy chain complementarity domain regions (CDRs) of HM14c10, while fewer interactions are observed with its light chain than for the E protein. We show that E1 can be utilized to detect HM14c10-like antibodies in sera from patients who recovered from DENV-1, infection suggesting that this is a public (common) idiotype. These data demonstrate the utility of employing an anti-idiotype antibody to monitor a patient's specific immune responses and suggest routes for the improvement of E "mimicry" by E1 by increasing its recognition of the Fab HM14c10 light chain CDRs.IMPORTANCE A chimeric yellow fever-dengue live-attenuated tetravalent vaccine is now being marketed. Dengue remains a significant public health problem, because protection conferred by this vaccine against the four circulating serotypes is uneven. Reliable tools must be developed to measure the immune responses of individuals exposed to DENV either via viral infection or through vaccination. Anti-idiotypic antibodies provide precision tools for analyzing the pharmacokinetics of antibodies in an immune response and also for measuring the amount of circulating anti-infective therapeutic antibodies. Here, we characterize how an anti-idiotypic antibody (E1) binds antibody HM14c10, which potently neutralizes DENV serotype 1. We report the crystal structure at a resolution of 2.5 Å of a complex between the Fab fragments of E1 and HM14c10 and provide the first detailed molecular comparison between the anti-idiotype surface and its analogous epitope located at the surface of the dengue virus particle.

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Section: Resultssupporting

confidence: 63%

Structural Mimicry of the Dengue Virus Envelope Glycoprotein Revealed by the Crystallographic Study of an Idiotype–Anti-idiotype Fab Complex

Wong

Goh

Lim

et al. 2017

J Virol

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“…These complexes will define: (i) the antigenic determinant; (ii) the functional Ab combining site and the idiotope; and (iii) a possible mimicry of the antigen by the anti-Id. Several anti-Id Ab and Id-anti-Id complexes have been studied by x-ray crystallographic techniques (20)(21)(22)(23)(24). In these systems (9), the structure of the external antigen (21,23) or of the Id-anti-Id complex (21,22,24) or of the Ab1-antigen complex (21-23) was not known.…”

Section: Discussionmentioning

confidence: 99%

Characterization of anti-anti-idiotypic antibodies that bind antigen and an anti-idiotype

Goldbaum

Velikovsky

Dall’Acqua³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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Two mouse monoclonal anti-anti-idiotopic antibodies (anti-anti-Id, Ab3), AF14 and AF52, were prepared by immunizing BALB͞c mice with rabbit polyclonal antiidiotypic antibodies (anti-Id, Ab2) raised against antibody D1.3 (Ab1) specific for the antigen hen egg lysozyme. AF14 and AF52 react with an ''internal image'' monoclonal mouse anti-Id antibody E5.2 (Ab2), previously raised against D1.3, with affinity constants (1.0 ؋ 10 9 M ؊1 and 2.4 ؋ 10 7 M ؊1 , respectively) usually observed in secondary responses against protein antigens. They also react with the antigen but with lower affinity (1.8 ؋ 10 6 M ؊1 and 3.8 ؋ 10 6 M ؊1 ). This pattern of affinities for the anti-Id and for the antigen also was displayed by the sera of the immunized mice. The amino acid sequences of AF14 and AF52 are very close to that of D1.3. In particular, the amino acid side chains that contribute to contacts with both antigen and anti-Id are largely conserved in AF14 and AF52 compared with D1.3. Therapeutic immunizations against different pathogenic antigens using anti-Id antibodies have been proposed. Our experiments show that a response to an anti-Id immunogen elicits anti-anti-Id antibodies that are optimized for binding the anti-Id antibodies rather than the antigen.The complementarity determining regions (CDR) of Ab display great structural diversity and constitute a vast array of potential antigenic determinants. Under appropriate experimental conditions, these determinants give rise to immune responses and are called idiotypic (1, 2). Idiotypes of Ab are the sum of idiotopes (Id) or antigenic determinants characterized experimentally by the reaction of an anti-idiotopic (anti-Id) antibody (Ab2) with the Id (Ab1). In most cases, idiotypes have been shown to be associated, partially or entirely, with the CDR of Ab molecules (3).The observation that external antigens and anti-Id Ab can competitively bind to specific Ab has led to proposals that anti-Id Ab may carry an ''internal image'' (2) of the external antigen. Functional mimicry of ligands of biological receptors by anti-Id Ab has been described in several systems (4). The potential for mimicking external antigens has led to proposals (5, 6) to use anti-idiotypic Ab as surrogate antigens. Recent reviews (7-9) have discussed this topic from a structural viewpoint. Indeed, anti-Id Ab have been used in exploring therapeutic immunizations against different pathogenic antigens.A report from this laboratory compared the threedimensional structures of the complexes between an Ab1-antigen and an Ab1-anti-Id and provided a concrete example of how an anti-Id Ab can structurally mimic an external antigen (10, 11). In this system, the Ab1 was the mAb D1.3 specific for the antigen, hen egg lysozyme (HEL). The three-dimensional crystal structure of the complex between the Fv fragment of D1.3 with HEL has been determined at the resolution of 1.8 Å (12). Subsequently, the three-dimensional structure of a complex between the Fv from D1.3 and the anti-Id Fv from mAb E5.2 (the Ab2; BALB͞c I...

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“…It has been suggested that a single CDR loop may mimic a ligand or antigen, 34 and sequence homology with antigen of V H and V L CDR segments in an anti-idiotypic antibody have been noted previously. 35 Specificity and affinity of cc␣Id Displacement ELISA of cc␣Id Fab-phage confirmed that the Fab binds to the antigen binding site of MAT/HAT because: (1) cc␣Id phage bind to both HAT and MAT; (2) phage binding to either HAT or MAT is displaced by either HAT or MAT; and (3) phage binding to either HAT or MAT is displaced by sTac ( Figure 5). Less than quantitative displacement by ligand may be due to affinity-enhanced binding by phage that displays Ͼ monovalent Fab, particularly for sTac which can only bind monovalently.…”

Section: Figurementioning

confidence: 85%

Examination of a role for idiotypy in the disease remission of a long-term survivor of adult T cell leukemia treated with anti-Tac antibody

1998

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The alpha chain of the interleukin 2 receptor (IL2R␣; Tac) was targeted in clinical trials with adult T cell leukemia using murine anti-Tac antibody. Of 19 patients, a single individual achieved a durable complete remission. The mechanism of this action by murine anti-Tac has not been defined. We examined the hypothesis that the maintenance of the long-term response after treatment might be related to induction of a network of anti-idiotypic antibodies, as proposed in other tumor settings. In contrast to anti-Tac non-responders, the patient was found to have produced a human anti-mouse antibody (HAMA) response, and specifically an anti-idiotypic (

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Crystal structure of an idiotype-anti-idiotype Fabcomplex.

Cited by 99 publications

References 27 publications

Structural Mimicry of the Dengue Virus Envelope Glycoprotein Revealed by the Crystallographic Study of an Idiotype–Anti-idiotype Fab Complex

Structural Mimicry of the Dengue Virus Envelope Glycoprotein Revealed by the Crystallographic Study of an Idiotype–Anti-idiotype Fab Complex

Characterization of anti-anti-idiotypic antibodies that bind antigen and an anti-idiotype

Examination of a role for idiotypy in the disease remission of a long-term survivor of adult T cell leukemia treated with anti-Tac antibody

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