By accepting you will be accessing a service provided by a third-party external to https://mschristian.org/

Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding site

Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding site
 2020 Jan-Dec;12(1):1713648. doi: 10.1080/19420862.2020.1713648.

Abstract

LINGO-1 is a membrane protein of the central nervous system (CNS) that suppresses myelination of axons. Preclinical studies have revealed that blockade of LINGO-1 function leads to CNS repair in demyelinating animal models. The anti-LINGO-1 antibody Li81 (opicinumab), which blocks LINGO-1 function and shows robust remyelinating activity in animal models, is currently being investigated in a Phase 2 clinical trial as a potential treatment for individuals with relapsing forms of Multiple Sclerosis (AFFINITY: clinical trial.gov number NCT03222973). 

Li81 has the unusual feature that it contains two LINGO-1 binding sites: a classical site utilizing its complementarity-determining regions and a cryptic secondary site involving Li81 light chain framework residues that recruits a second LINGO-1 molecule only after engagement of the primary binding site. Concurrent binding at both sites leads to formation of a 2:2 complex of LINGO-1 with the Li81 antigen-binding fragment, and higher order complexes with intact Li81 antibody. To elucidate the role of the secondary binding site, we designed a series of Li81 variant constructs that eliminate it while retaining the classic site contacts. These Li81 mutants retained the high affinity binding to LINGO-1, but lost the antibody-induced oligodendrocyte progenitor cell (OPC) differentiation activity and myelination activity in OPC- dorsal root ganglion neuron cocultures seen with Li81. The mutations also attenuate antibody-induced internalization of LINGO-1 on cultured cortical neurons, OPCs, and cells over-expressing LINGO-1. Together these studies reveal that engagement at both LINGO-1 binding sites of Li81 is critical for robust functional activity of the antibody.

CLICK HERE to see a visual of the above


PMID: 31928294 PMCID: PMC6973334 DOI: 10.1080/19420862.2020.1713648




.................................................................................................

CLICK Red BOX to SUBSCRIBE to the MS Learning Channel on YouTube

weigh
Click Red Box on banner to opt-in
........................................................................................................

This Article is Provided by:  #MSViewsandNews
::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::
Visit our MS Learning Channel on YouTube: http://www.youtube.com/msviewsandnews
weigh
(Originally posted by Stuart)
Survey: Teenage vaping epidemic concern could be ‘...
'Treat Them Like Human Beings': What We Heard This...
 

Comments

No comments made yet. Be the first to submit a comment
Already Registered? Login Here
Guest
Sunday, 05 July 2020

Captcha Image


MSChristian.org RSS Statement

Most of the information found on this website comes from RSS Feeds. It is an automated task that provides the information to you. We try to limit items that are duplicates, but with many feeds this can be difficult. Since the owner of this website also has MS and is legally blind this service was necessary to keep the website running with as much automation as possible. Volunteers help from time to time but many have disabilities themselves. We thank you for visiting us and hope that MSC can be of service to you and your loved ones.