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Molecular Flexibility of Antibodies Preserved even in the Dense Phase after Macroscopic Phase Separation

Girelli, Anita ; Beck, Christian ; Bäuerle, Famke ; Matsarskaia, Olga ; Maier, Ralph ; Zhang, Fajun LU ; Wu, Baohu ; Lang, Christian ; Czakkel, Orsolya and Seydel, Tilo , et al. (2021) In Molecular Pharmaceutics 18(11). p.4162-4169
Abstract

Antibody therapies are typically based on high-concentration formulations that need to be administered subcutaneously. These conditions induce several challenges, inter alia a viscosity suitable for injection, sufficient solution stability, and preservation of molecular function. To obtain systematic insights into the molecular factors, we study the dynamics on the molecular level under strongly varying solution conditions. In particular, we use solutions of antibodies with poly(ethylene glycol), in which simple cooling from room temperature to freezing temperatures induces a transition from a well-dispersed solution into a phase-separated and macroscopically arrested system. Using quasi-elastic neutron scattering during in situ cooling... (More)

Antibody therapies are typically based on high-concentration formulations that need to be administered subcutaneously. These conditions induce several challenges, inter alia a viscosity suitable for injection, sufficient solution stability, and preservation of molecular function. To obtain systematic insights into the molecular factors, we study the dynamics on the molecular level under strongly varying solution conditions. In particular, we use solutions of antibodies with poly(ethylene glycol), in which simple cooling from room temperature to freezing temperatures induces a transition from a well-dispersed solution into a phase-separated and macroscopically arrested system. Using quasi-elastic neutron scattering during in situ cooling ramps and in prethermalized measurements, we observe a strong decrease in antibody diffusion, while internal flexibility persists to a significant degree, thus ensuring the movement necessary for the preservation of molecular function. These results are relevant for a more dynamic understanding of antibodies in high-concentration formulations, which affects the formation of transient clusters governing the solution viscosity.

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publishing date
type
Contribution to journal
publication status
published
keywords
antibody therapy, diffusion, dynamics, molecular flexibility
in
Molecular Pharmaceutics
volume
18
issue
11
pages
8 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:34637319
  • scopus:85118114235
ISSN
1543-8384
DOI
10.1021/acs.molpharmaceut.1c00555
language
English
LU publication?
no
id
7f6102b4-446f-49ac-9255-0566c6706c90
date added to LUP
2023-08-14 10:27:56
date last changed
2024-04-05 22:08:48
@article{7f6102b4-446f-49ac-9255-0566c6706c90,
  abstract     = {{<p>Antibody therapies are typically based on high-concentration formulations that need to be administered subcutaneously. These conditions induce several challenges, inter alia a viscosity suitable for injection, sufficient solution stability, and preservation of molecular function. To obtain systematic insights into the molecular factors, we study the dynamics on the molecular level under strongly varying solution conditions. In particular, we use solutions of antibodies with poly(ethylene glycol), in which simple cooling from room temperature to freezing temperatures induces a transition from a well-dispersed solution into a phase-separated and macroscopically arrested system. Using quasi-elastic neutron scattering during in situ cooling ramps and in prethermalized measurements, we observe a strong decrease in antibody diffusion, while internal flexibility persists to a significant degree, thus ensuring the movement necessary for the preservation of molecular function. These results are relevant for a more dynamic understanding of antibodies in high-concentration formulations, which affects the formation of transient clusters governing the solution viscosity.</p>}},
  author       = {{Girelli, Anita and Beck, Christian and Bäuerle, Famke and Matsarskaia, Olga and Maier, Ralph and Zhang, Fajun and Wu, Baohu and Lang, Christian and Czakkel, Orsolya and Seydel, Tilo and Schreiber, Frank and Roosen-Runge, Felix}},
  issn         = {{1543-8384}},
  keywords     = {{antibody therapy; diffusion; dynamics; molecular flexibility}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{11}},
  pages        = {{4162--4169}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Molecular Pharmaceutics}},
  title        = {{Molecular Flexibility of Antibodies Preserved even in the Dense Phase after Macroscopic Phase Separation}},
  url          = {{http://dx.doi.org/10.1021/acs.molpharmaceut.1c00555}},
  doi          = {{10.1021/acs.molpharmaceut.1c00555}},
  volume       = {{18}},
  year         = {{2021}},
}