The Intrinsic Contributions of Tyrosine, Serine, Glycine and Arginine to the Affinity and Specificity of Antibodies

Birtalan, Sara; Zhang, Yingnan; Fellouse, Frédéric A.; Shao, Lihua; Schaefer, Gabriele; Sidhu, Sachdev S.

doi:10.1016/j.jmb.2008.01.093

Cited by 208 publications

(203 citation statements)

References 42 publications

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“…In addition, Asn I27 forms a hydrogen bond with Trp H31 . These results are in agreement with the notion that tyrosine is the most frequently observed residue in the CDRs and plays the most important role in the Ag/Ab interaction because it can form both hydrophobic and hydrogen bonding interactions (54)(55)(56).…”

Section: Resultssupporting

confidence: 92%

Structural Basis for the Blockage of IL-2 Signaling by Therapeutic Antibody Basiliximab

Zhang

et al. 2009

The Journal of Immunology

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IL-2 signaling plays a central role in the initiation and activation of immune responses. Correspondingly, blockage of this pathway leads to inhibition of the immune system and would provide some therapeutic benefits. Basiliximab (Simulect), a therapeutic mAb drug with specificity against IL-2Rα of T cells, was approved by U.S. Food and Drug Administration in 1998. It has been proven to be effective in the suppression of the IL-2 pathway and hence has been widely used to prevent allograft rejection in organ transplantation, especially in kidney transplants. In this study, we report the crystal structure of the basiliximab Fab in complex with the ectodomain of IL-2Rα at 2.9 Å resolution. In the complex structure, the Fab interacts with IL-2Rα with extensive hydrophobic and hydrophilic interactions, accounting for a high binding affinity of 0.14 nM. The Ag binding site of basiliximab consists of all six CDR loops that form a large binding interface with a central shallow hydrophobic groove surrounded by four hydrophilic patches. The discontinuous epitope is composed of several segments from the D1 domain and a minor segment from the D2 domain that overlap with most of the regions responsible for the interactions with IL-2. Thus, basiliximab binding can completely block the interactions of IL-2 with IL-2Rα and hence inhibit the activation of the IL-2 signal pathway. The structural results also provide important implications for the development of improved and new IL-2Rα–targeted mAb drugs.

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Section: Resultssupporting

confidence: 92%

Structural Basis for the Blockage of IL-2 Signaling by Therapeutic Antibody Basiliximab

Zhang

et al. 2009

The Journal of Immunology

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“…Looking at the cause of nonspecificity in briakinumab, the charge dependence of this phenotype was consistent with our BLI experiments, and is consistent with previous findings that positively charged patches can lead to increased nonspecific binding to cells and other proteins. 12,18,[38][39][40] These results are also consistent with a similar study using the IgG4 isotype, in which a higher pI led to a shortened half-life and higher clearance rates regardless of presence of FcRn. 15 Studies on larger sets of antibodies suggest that the correlation between pI and clearance rates is not generalizable; 24,25 however, a localized patch of positive charge may be sufficient to increase interactions with the negatively charged surface of cell membranes.…”

Section: Discussionsupporting

confidence: 90%

Target-independent variable region mediated effects on antibody clearance can be FcRn independent

Kelly

Sun

et al. 2016

mAbs

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The importance of the neonatal Fc receptor (FcRn) in extending the serum half-life of monoclonal antibodies (mAbs) is well demonstrated, and has led to the development of multiple engineering approaches designed to alter Fc interactions with FcRn. Recent reports have additionally highlighted the effect of nonspecific interactions on antibody pharmacokinetics (PK), suggesting an FcRn-independent mechanism for mAb clearance. In this report we examine a case study of 2 anti-interleukin-12/23 antibodies, ustekinumab and briakinumab, which share the same target and Fc, but differ in variable region sequences. Ustekinumab displayed near baseline signal in a wide range of early stage developability assays for undesirable protein/protein interactions, while briakinumab showed significant propensity for self-and cross-interactions. This phenotypic difference correlates with faster clearance rates for briakinumab in both human FcRn transgenic and FcRn knockout mice. These findings support a dominant contribution for FcRn-independent clearance for antibodies with high nonspecificity, and highlight a key role for early stage developability screening to eliminate clones with such high nonspecific disposition PK.

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“…6A, the top five amino acids for antibodies are serine, glycine, tyrosine, threonine, and asparagine. The physicochemical basis for antibody enrichment in these amino acids is well understood (47,48). The distribution in TCR germ-line loops resembles that in antibodies, but with some distinctions.…”

Section: Evolution Has Enhanced the Ability Of Tcr Germ-line Loops Tomentioning

confidence: 99%

How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire

Blevins

Pierce

Singh

et al. 2016

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

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How T-cell receptors (TCRs) can be intrinsically biased toward MHC proteins while simultaneously display the structural adaptability required to engage diverse ligands remains a controversial puzzle. We addressed this by examining αβ TCR sequences and structures for evidence of physicochemical compatibility with MHC proteins. We found that human TCRs are enriched in the capacity to engage a polymorphic, positively charged "hot-spot" region that is almost exclusive to the α1-helix of the common human class I MHC protein, HLA-A*0201 (HLA-A2). TCR binding necessitates hot-spot burial, yielding high energetic penalties that must be offset via complementary electrostatic interactions. Enrichment of negative charges in TCR binding loops, particularly the germ-line loops encoded by the TCR Vα and Vβ genes, provides this capacity and is correlated with restricted positioning of TCRs over HLA-A2. Notably, this enrichment is absent from antibody genes. The data suggest a built-in TCR compatibility with HLA-A2 that biases receptors toward, but does not compel, particular binding modes. Our findings provide an instructional example for how structurally pliant MHC biases can be encoded within TCRs.T-cell receptor | peptide/MHC | structure | binding | MHC bias

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The Intrinsic Contributions of Tyrosine, Serine, Glycine and Arginine to the Affinity and Specificity of Antibodies

Cited by 208 publications

References 42 publications

Structural Basis for the Blockage of IL-2 Signaling by Therapeutic Antibody Basiliximab

Structural Basis for the Blockage of IL-2 Signaling by Therapeutic Antibody Basiliximab

Target-independent variable region mediated effects on antibody clearance can be FcRn independent

How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire

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