Evidence map›Paper›PMID 30102763›Full record

ArticleBiotechnology and bioengineering2018

Epitope-specific affinity maturation improved stability of potent protease inhibitory antibodies.

Tyler Lopez, Chen Chuan, Aaron Ramirez, Kuan-Hui E Chen, Mary Y Lorenson, Chris Benitez, Zahid Mustafa, Henry Pham, Ramon Sanchez, Ameae M Walker and 1 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Biotechnology and bioengineering, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed.

  1. Article
  2. Functional selection of protease inhibitory antibodies.Proceedings of the National Academy of Sciences of the United States of America · 2019
    Article
  3. Review
  4. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors.

Tyler LopezDepartment of Chemical and Environmental Engineering, Bourns College of Engineering, University of California Riverside, Riverside, California.
Chen ChuanDepartment of Chemical and Environmental Engineering, Bourns College of Engineering, University of California Riverside, Riverside, California.
Aaron RamirezDepartment of Chemical and Environmental Engineering, Bourns College of Engineering, University of California Riverside, Riverside, California.
Kuan-Hui E ChenDivision of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California.
Mary Y LorensonDivision of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California.
Chris BenitezDepartment of Chemical and Environmental Engineering, Bourns College of Engineering, University of California Riverside, Riverside, California.
Zahid MustafaDepartment of Chemical and Environmental Engineering, Bourns College of Engineering, University of California Riverside, Riverside, California.
Henry PhamDepartment of Chemical and Environmental Engineering, Bourns College of Engineering, University of California Riverside, Riverside, California.
Ramon SanchezDepartment of Chemical and Environmental Engineering, Bourns College of Engineering, University of California Riverside, Riverside, California.
Ameae M WalkerDivision of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California.
Xin GeDepartment of Chemical and Environmental Engineering, Bourns College of Engineering, University of California Riverside, Riverside, California.ORCID 0000-0001-7491-7805

Funding

Structure-based design of camel-like human selective mAbs against MMPs in diseaseR01GM115672 · NIGMS · UNIVERSITY OF CALIFORNIA RIVERSIDE · PI GE, XIN · 2016 to 2020
$1.5M
NIGMS NIH HHS R01 GM115672
6 · The paper itself

Abstract

Targeting effectual epitopes is essential for therapeutic antibodies to accomplish their desired biological functions. This study developed a competitive dual color fluorescence-activated cell sorting (FACS) to maturate a matrix metalloprotease 14 (MMP-14) inhibitory antibody. Epitope-specific screening was achieved by selection on MMP-14 during competition with N-terminal domain of tissue inhibitor of metalloproteinase-2 (TIMP-2) (nTIMP-2), a native inhibitor of MMP-14 binding strongly to its catalytic cleft. 3A2 variants with high potency, selectivity, and improved affinity and proteolytic stability were isolated from a random mutagenesis library. Binding kinetics indicated that the affinity improvements were mainly from slower dissociation rates. In vitro degradation tests suggested the isolated variants had half lives 6-11-fold longer than the wt. Inhibition kinetics suggested they were competitive inhibitors which showed excellent selectivity toward MMP-14 over highly homologous MMP-9. Alanine scanning revealed that they bound to the vicinity of MMP-14 catalytic cleft especially residues F204 and F260, suggesting that the desired epitope was maintained during maturation. When converted to immunoglobulin G, B3 showed 5.0 nM binding affinity and 6.5 nM inhibition potency with in vivo half-life of 4.6 days in mice. In addition to protease inhibitory antibodies, the competitive FACS described here can be applied for discovery and engineering biosimilars, and in general for other circumstances where epitope-specific modulation is needed.

Indexed as

Antibody AffinityAnimalsAntibodiesBinding SitesDrug Evaluation, PreclinicalEpitopesFlow CytometryHalf-LifeImmunologic FactorsKineticsMatrix Metalloproteinase 14Matrix Metalloproteinase InhibitorsMiceMutagenesisProtein BindingAntibodiesEpitopesImmunologic FactorsMatrix Metalloproteinase 14Matrix Metalloproteinase Inhibitorsepitope specificityFACSinhibitory antibodyMMPproteolytic stability

Identifiers

PMID30102763
PMCPMC6202216

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.