Human CD4 mimicry by anti-idiotypic monoclonal antibody 16D7 is based on a conformational epitope

Perosa, Federico; Favoino, Elvira; Caragnano, Maria Antonietta; Dammacco, Franco

doi:10.1016/j.imlet.2004.06.012

Cited by 3 publications

(1 citation statement)

References 21 publications

(19 reference statements)

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“…A wide variety of studies indicate that bioactive peptides can be generated using sequence information of antibody variable domains (Saragovi et al, 1991;Williams et al, 1991;Monnet et al, 1999;Levi et al, 1993Levi et al, , 2000Park et al, 2000;Laune et al, 1997Laune et al, , 2002Berezov et al, 2001;Tsumoto et al, 2002;Feng et al, 1998Feng et al, , 2005Bè s et al, 2001Bè s et al, , 2003Casset et al, 2003;Perosa et al, 2004; (wileyonlinelibrary.com) DOI:10.1002/jmr.1017 Heap et al, 2005). However, little experimental data are available to demonstrate that such peptides do indeed reproduce the structure and binding mode of the corresponding antibody paratope.…”

Section: Introductionmentioning

confidence: 99%

Binding of CDR‐derived peptides is mechanistically different from that of high‐affinity parental antibodies

Timmerman

Shochat

Desmet

et al. 2010

J of Molecular Recognition

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We present data that reveal crucial differences between the binding mode of anti-gastrin17 (G17, pyroEGPW-LEEEEEAYGWMDF-NH 2 ) monoclonal antibodies (mAbs) and their CDR-derived synthetic binders (SBs) with G17. The mAbs recognize the N-terminal sequence of G17 ( pyroEGPWL) with nanomolar affinity and high sequence selectivity. Molecular simulations suggest that G17 recognition is based primarily on a multitude of weak antibody-ligand interactions (H-bonding, van der Waals, etc.) inside a structurally well-defined cleft-like binding pocket. Relatively small structural changes (e.g. G-2 to A for G17) have a drastic impact on affinity, which is characteristic for antibody-like binding. In contrast, SBs recognize various sequences, including G17-unrelated targets with affinities of 1:1 complexes estimated in the 0.1-1.0 mM range. In most cases however, the G17/SB complex stoichiometries are not well-defined, giving rise to multimer aggregate formation with high apparent complex stabilities. Mutational studies on both G17 and SBs reveal the importance of positively charged (K/R) and aromatic residues (W/Y/F) for G17/SB complex formation. We propose that the synthetic binders use combinations of electrostatic, hydrophobic, and/or cation-p interactions in a variety of ways due to their intrinsic flexibility. This may also be the reason for their relatively low target specificity. We speculate that our findings are of general relevance, in showing that high-affinity mAbs do not necessarily provide the optimal basis for functional mimics design.

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Section: Introductionmentioning

confidence: 99%

Binding of CDR‐derived peptides is mechanistically different from that of high‐affinity parental antibodies

Timmerman

Shochat

Desmet

et al. 2010

J of Molecular Recognition

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Downsizing antibodies: Towards complementarity-determining region (CDR)-based peptide mimetics

holsbeeck

Martins

Ballet

2022

Bioorganic Chemistry

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Computational Identification of Antigen-Binding Antibody Fragments

Burkovitz

Leiderman

Sela-Culang

et al. 2013

The Journal of Immunology

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Determining which parts of the Ab are essential for Ag recognition and binding is crucial for understanding B cell–mediated immunity. Identification of fragments of Abs that maintain specificity to the Ag will also allow for the development of improved Ab-based therapy and diagnostics. In this article, we show that structural analysis of Ab–Ag complexes reveals which fragments of the Ab may bind the Ag on their own. In particular, it is possible to predict whether a given CDR is likely to bind the Ag as a peptide by analyzing the energetic contribution of each CDR to Ag binding and by assessing to what extent the interaction between that CDR and the Ag depends on other CDRs. To demonstrate this, we analyzed five Ab–Ag complexes and predicted for each of them which of the CDRs may bind the Ag on its own as a peptide. We then show that these predictions are in agreement with our experimental analysis and with previously published experimental results. These findings promote our understanding of the modular nature of Ab–Ag interactions and lay the foundation for the rational design of active CDR-derived peptides.

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Human CD4 mimicry by anti-idiotypic monoclonal antibody 16D7 is based on a conformational epitope

Cited by 3 publications

References 21 publications

Binding of CDR‐derived peptides is mechanistically different from that of high‐affinity parental antibodies

Binding of CDR‐derived peptides is mechanistically different from that of high‐affinity parental antibodies

Downsizing antibodies: Towards complementarity-determining region (CDR)-based peptide mimetics

Computational Identification of Antigen-Binding Antibody Fragments

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