Improving Antibody Binding Affinity and Specificity for Therapeutic Development

2008 ◽  
pp. 353-376 ◽  
Author(s):  
Jenny Bostrom ◽  
Chingwei V. Lee ◽  
Lauric Haber ◽  
Germaine Fuh
Keyword(s):  
Binding Affinity ◽  
Antibody Binding ◽  
Therapeutic Development

scholarly journals Enhanced tumor-targeting selectivity by modulating bispecific antibody binding affinity and format valence

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Yariv Mazor ◽  
Kris F. Sachsenmeier ◽  
Chunning Yang ◽  
Anna Hansen ◽  
Jessica Filderman ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Tumor Targeting ◽  
Bispecific Antibody ◽  
Antibody Binding

scholarly journals Differences in the Binding Affinity of an HIV-1 V2 Apex-Specific Antibody for the SIVsmm/macEnvelope Glycoprotein Uncouple Antibody-Dependent Cellular Cytotoxicity from Neutralization

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Benjamin von Bredow ◽  
Raiees Andrabi ◽  
Michael Grunst ◽  
Andres G. Grandea ◽  
Khoa Le ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Specific Antibody ◽  
Neutralizing Antibody ◽  
Glycosylation Site ◽  
Antibody Binding ◽  
Cellular Cytotoxicity ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Broadly Neutralizing Antibody ◽  
Infected Cells ◽  
Hiv 1

ABSTRACTAs a consequence of their independent evolutionary origins in apes and Old World monkeys, human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency viruses of the SIVsmm/maclineage express phylogenetically and antigenically distinct envelope glycoproteins. Thus, HIV-1 Env-specific antibodies do not typically cross-react with the Env proteins of SIVsmm/macisolates. Here we show that PGT145, a broadly neutralizing antibody to a quaternary epitope at the V2 apex of HIV-1 Env, directs the lysis of SIVsmm/mac-infected cells by antibody-dependent cellular cytotoxicity (ADCC) but does not neutralize SIVsmm/macinfectivity. Amino acid substitutions in the V2 loop of SIVmac239 corresponding to the epitope for PGT145 in HIV-1 Env modulate sensitivity to this antibody. Whereas a substitution in a conserved N-linked glycosylation site (N171Q) eliminates sensitivity to ADCC, a lysine-to-serine substitution in this region (K180S) increases ADCC and renders the virus susceptible to neutralization. These differences in function correlate with an increase in the affinity of PGT145 binding to Env on the surface of virus-infected cells and to soluble Env trimers. To our knowledge, this represents the first instance of an HIV-1 Env-specific antibody that cross-reacts with SIVsmm/macEnv and illustrates how differences in antibody binding affinity for Env can differentiate sensitivity to ADCC from neutralization.IMPORTANCEHere we show that PGT145, a potent broadly neutralizing antibody to HIV-1, directs the lysis of SIV-infected cells by antibody-dependent cellular cytotoxicity but does not neutralize SIV infectivity. This represents the first instance of cross-reactivity of an HIV-1 Env-specific antibody with SIVsmm/macEnv and reveals that antibody binding affinity can differentiate sensitivity to ADCC from neutralization.

scholarly journals Analysis of a Highly Flexible Conformational Immunogenic Domain A in Hepatitis C Virus E2

2005 ◽  
Vol 79 (21) ◽  
pp. 13199-13208 ◽  
Author(s):  
Zhen-Yong Keck ◽  
Ta-Kai Li ◽  
Jinming Xia ◽  
Birke Bartosch ◽  
François-Loïc Cosset ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Binding Affinity ◽  
Structural Changes ◽  
Low Ph ◽  
Antibody Binding ◽  
Spatial Proximity ◽  
Neutralizing Activity ◽  
Isolation And Characterization ◽  
Structural And Functional Properties

ABSTRACT Hepatitis C (HCV) E2 glycoprotein is involved in virus attachment and entry, and its structural organization is largely unknown. Characterization of a panel of human monoclonal antibodies (HMAbs) to HCV by competition studies has led to an immunogenic organization model of E2 with three domains designated A, B, and C and epitopes in each domain having similar structural and functional properties. Domain A contains nonneutralizing epitopes, and domains B and C contain neutralizing epitopes. The isolation and characterization of three new HMAbs within domain A for a total of six provide support for this model. All six domain A HMAbs do not neutralize HCV retroviral pseudotype particle (HCVpp) infection on Huh-7 cells, and all six HMAbs have similar binding affinity and maximum binding, B max, a relative indicator of epitope density, as other neutralizing HMAbs, suggesting that neutralization is epitope specific and not by binding to any surface epitope. The dose-dependent neutralizing activity of CBH-7, an HMAb to a domain C epitope in spatial proximity to domain A, and of CBH-5, a domain B HMAb to a more distant epitope, were tested in the presence and absence of each domain A HMAb. No enhancement or reduction in CBH-7 or CBH-5 neutralizing activity was observed, indicating that the potential induction of nonneutralizing antibodies should not be a central issue for HCV vaccine design. To assess whether domain A is involved in the structural changes as part of a pH-dependent virus envelope fusion process, changes in antibody binding patterns to normal pH and acid pH-treated HCVpp were measured. Antibody binding affinity of HMAbs to HCVpp was not affected by low pH. However, the B max values for low-pH-treated HCVpp with antibodies to domain A increased 46%, for domain C (CBH-7) they increased 23%, and for domain B (CBH-5) there was a decrease of 12%. Collectively, the organization and function of HCV E2 antigenic domains are roughly analogous to the large envelope glycoprotein E organizational structure for other flaviviruses with three distinct structural and functional domains.

Structure of the DNA (6–4) photoproduct dTT(6–4)TT in complex with the 64M-2 antibody Fab fragment implies increased antibody-binding affinity by the flanking nucleotides

2012 ◽  
Vol 68 (3) ◽  
pp. 232-238 ◽  
Author(s):  
Hideshi Yokoyama ◽  
Ryuta Mizutani ◽  
Yoshinori Satow ◽  
Kousuke Sato ◽  
Yasuo Komatsu ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Antibody Binding ◽  
Fab Fragment

scholarly journals Determination of Antibody Binding Affinity using Single-Molecule Counting and Flow

2016 ◽  
Vol 110 (3) ◽  
pp. 492a
Author(s):  
Patrick J. Macdonald ◽  
Qiaoqiao Ruan ◽  
Richard A. Haack ◽  
Sergey Y. Tetin
Keyword(s):  
Binding Affinity ◽  
Single Molecule ◽  
Antibody Binding

Enhanced antigen-antibody binding affinity mediated by an anti-idiotypic antibody

Biochemistry ◽  
1987 ◽  
Vol 26 (17) ◽  
pp. 5275-5282 ◽  
Author(s):  
David G. Sawutz ◽  
Richard Koury ◽  
Charles J. Homcy
Keyword(s):  
Binding Affinity ◽  
Antibody Binding ◽  
Antigen Antibody ◽  
Idiotypic Antibody

scholarly journals Folding in Place: Design of β-Strap Motifs to Stabilize the Folding of Hairpins with Long Loops

2020 ◽  
Author(s):  
Alexis Richaud ◽  
Guangkuan zhao ◽  
Stephane Roche ◽  
Samir Hobloss
Keyword(s):  
Thermal Stability ◽  
Binding Affinity ◽  
Protein Function ◽  
Antibody Binding ◽  
Attractive Alternative ◽  
Stability Behavior ◽  
Cooperative Interactions ◽  
Spectroscopic Probes ◽  
Macrocyclic Peptides ◽  
Present Design

Despite their pivotal role in protein function and antibody binding affinity, <i>β</i>-hairpins bearing long non-canonical loops are a challenge to modern synthesis because of the large entropic penalty associated with their folding. Little is known about the contribution and impact of stabilizing motifs on the folding of <i>β</i>-hairpins of variable length and plasticity. Here we report a direct comparison between these <i>b</i>-straps thermodynamics and their thermal stability behavior using several local spectroscopic probes of the folding/unfolding landscape. The judicious cooperative interactions crafted in <i>β</i>-Strap <u>R</u>W(<u>V</u>W)•••(W<u>V</u>/<u>H</u>)W<u>E</u> (<i>strap</i> = <i>str</i>and + c<i>ap</i>) greatly stabilized hairpins with up to 10-residue loops lacking an innate nucleating-turn locus (<i>T<sub>m</sub> </i>up to 52 <sup>o</sup>C; 88 ± 1% folded at 291 K). The present design of novel <i>β</i>-straps aims to provide the foundation to study new classes of long hairpins and ultimately offer an attractive alternative to macrocyclic peptides for the mimicry of functional loops from proteins and antibodies.

scholarly journals Folding in Place: Design of β-Strap Motifs to Stabilize the Folding of Hairpins with Long Loops

2021 ◽  
Author(s):  
Alexis Richaud ◽  
Guangkuan zhao ◽  
Stephane Roche ◽  
Samir Hobloss
Keyword(s):  
Thermal Stability ◽  
Binding Affinity ◽  
Protein Function ◽  
Antibody Binding ◽  
Attractive Alternative ◽  
Stability Behavior ◽  
Cooperative Interactions ◽  
Spectroscopic Probes ◽  
Macrocyclic Peptides ◽  
Present Design

Despite their pivotal role in protein function and antibody binding affinity, <i>β</i>-hairpins bearing long non-canonical loops are a challenge to modern synthesis because of the large entropic penalty associated with their folding. Little is known about the contribution and impact of stabilizing motifs on the folding of <i>β</i>-hairpins of variable length and plasticity. Here we report a direct comparison between these <i>b</i>-straps thermodynamics and their thermal stability behavior using several local spectroscopic probes of the folding/unfolding landscape. The judicious cooperative interactions crafted in <i>β</i>-Strap <u>R</u>W(<u>V</u>W)•••(W<u>V</u>/<u>H</u>)W<u>E</u> (<i>strap</i> = <i>str</i>and + c<i>ap</i>) greatly stabilized hairpins with up to 10-residue loops lacking an innate nucleating-turn locus (<i>T<sub>m</sub> </i>up to 52 <sup>o</sup>C; 88 ± 1% folded at 291 K). The present design of novel <i>β</i>-straps aims to provide the foundation to study new classes of long hairpins and ultimately offer an attractive alternative to macrocyclic peptides for the mimicry of functional loops from proteins and antibodies.

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