Antibody Variable Regions: Toward a Unified Modeling Method

Whitelegg, Nicholas R. J.; Rees, Anthony R.

doi:10.1385/1-59259-666-5:51

Cited by 15 publications

(24 citation statements)

References 20 publications

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“…Generally, the high homology to template structures typically results in precise homology models of framework and short CDR regions. However, modeling of long CDR loops is prone to large modeling uncertainties, possibly due to the high inherent flexibility of such loops [81]–[84]. Therefore, all CDRs were subjected to an additional loop modeling procedure [85] (Materials and Methods), yielding a five-membered homology model ensemble.…”

Section: Resultsmentioning

confidence: 99%

Structure-Based Prediction of Asparagine and Aspartate Degradation Sites in Antibody Variable Regions

Sydow¹,

Lipsmeier²,

Larraillet³

et al. 2014

PLoS ONE

139

159

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Monoclonal antibodies (mAbs) and proteins containing antibody domains are the most prevalent class of biotherapeutics in diverse indication areas. Today, established techniques such as immunization or phage display allow for an efficient generation of new mAbs. Besides functional properties, the stability of future therapeutic mAbs is a key selection criterion which is essential for the development of a drug candidate into a marketed product. Therapeutic proteins may degrade via asparagine (Asn) deamidation and aspartate (Asp) isomerization, but the factors responsible for such degradation remain poorly understood. We studied the structural properties of a large, uniform dataset of Asn and Asp residues in the variable domains of antibodies. Their structural parameters were correlated with the degradation propensities measured by mass spectrometry. We show that degradation hotspots can be characterized by their conformational flexibility, the size of the C-terminally flanking amino acid residue, and secondary structural parameters. From these results we derive an accurate in silico prediction method for the degradation propensity of both Asn and Asp residues in the complementarity-determining regions (CDRs) of mAbs.

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Section: Resultsmentioning

confidence: 99%

Structure-Based Prediction of Asparagine and Aspartate Degradation Sites in Antibody Variable Regions

Sydow¹,

Lipsmeier²,

Larraillet³

et al. 2014

PLoS ONE

139

159

View full text Add to dashboard Cite

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“…The remainder of the variable domains is structurally well conserved at the backbone level, and aligning antibody sequences is straightforward. For these reasons, a primary focus of antibody modeling is predicting the conformations of the CDR loops from their sequences (Whitelegg and Rees, 2004). …”

Section: Antibody Cdr Modelingmentioning

confidence: 99%

Computer-aided antibody design

Kuroda

Shirai

Jacobson

et al. 2012

Protein Engineering Design and Selection

219

151

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Recent clinical trials using antibodies with low toxicity and high efficiency have raised expectations for the development of next-generation protein therapeutics. However, the process of obtaining therapeutic antibodies remains time consuming and empirical. This review summarizes recent progresses in the field of computer-aided antibody development mainly focusing on antibody modeling, which is divided essentially into two parts: (i) modeling the antigen-binding site, also called the complementarity determining regions (CDRs), and (ii) predicting the relative orientations of the variable heavy (VH) and light (VL) chains. Among the six CDR loops, the greatest challenge is predicting the conformation of CDR-H3, which is the most important in antigen recognition. Further computational methods could be used in drug development based on crystal structures or homology models, including antibody–antigen dockings and energy calculations with approximate potential functions. These methods should guide experimental studies to improve the affinities and physicochemical properties of antibodies. Finally, several successful examples of in silico structure-based antibody designs are reviewed. We also briefly review structure-based antigen or immunogen design, with application to rational vaccine development.

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“…Most of the work in comparative modeling of antibodies has focused on modeling the CDR loops. [26][27][28][29] However, large differences in the relative orientation of the variable domains between different antibodies would require that the preferred V L :V H orientations of the target antibody sequence be explicitly considered, as has recently been done. 30 Because the V L :V H orientation appears to be a functionally important manifestation of antibody sequence diversity, one would expect to see significant variation in the orientation among existing antibody crystal structures.…”

Section: Introductionmentioning

confidence: 99%