Affordable Access

deepdyve-link deepdyve-link
Publisher Website

Designing cell-targeted therapeutic proteins reveals the interplay between domain connectivity and cell binding.

Authors
  • Robinson-Mosher, Avi
  • Chen, Jan-Hung
  • Way, Jeffrey
  • Silver, Pamela A
Type
Published Article
Journal
Biophysical Journal
Publisher
Elsevier
Publication Date
Nov 18, 2014
Volume
107
Issue
10
Pages
2456–2466
Identifiers
DOI: 10.1016/j.bpj.2014.10.007
PMID: 25418314
Source
Medline
License
Unknown

Abstract

The therapeutic efficacy of cytokines is often hampered by severe side effects due to their undesired binding to healthy cells. One strategy for overcoming this obstacle is to tether cytokines to antibodies or antibody fragments for targeted cell delivery. However, how to modulate the geometric configuration and relative binding affinity of the two domains for optimal activity remains an outstanding question. As a result, many antibody-cytokine complexes do not achieve the desired level of cell-targeted binding and activity. Here, we address these design issues by developing a computational model to simulate the dynamics and binding kinetics of natural and engineered fusion proteins such as antibody-cytokine complexes. To verify the model, we developed a modular system in which an antibody fragment and a cytokine are conjugated via a DNA linker that allows for programmable linker geometry and protein spatial configuration. By assembling and testing several anti-CD20 antibody fragment-interferon ? complexes, we showed that varying the linker length and cytokine binding affinity controlled the magnitude of cell-targeted signaling activation in a manner that agreed with the model predictions, which were expressed as dose-signaling response curves. The simulation results also revealed that there is a range of cytokine binding affinities that would achieve optimal therapeutic efficacy. This rapid prototyping platform will facilitate the rational design of antibody-cytokine complexes for improved therapeutic outcomes.

Report this publication

Statistics

Seen <100 times