Evidence map›Paper›PMID 33903632›Full record

ArticleScientific reports2021

Fc-GDF15 glyco-engineering and receptor binding affinity optimization for body weight regulation.

Ella Fung, Liya Kang, Diana Sapashnik, Susan Benard, Annette Sievers, Yan Liu, Guoying Yan, Jing Zhou, Linette Rodriguez, Weijun Ma and 12 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Scientific reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.

0numbers the graph read from it
0cells of the map it votes in
14citing papers in PubMed
2.2field-weighted citation impact, top 12% of its field
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

14 citing papers in PubMed, 19 citations in OpenAlex.

  1. Review
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  10. Article
  11. Whole-exome sequencing uncovers new variants in GDF15 associated with hyperemesis gravidarum.BJOG : an international journal of obstetrics and gynaecology · 2022
    Article
  12. Signaling pathways in obesity: mechanisms and therapeutic interventions.Signal transduction and targeted therapy · 2022
    Review
  13. Article
  14. GDF15: a potential therapeutic target for type 1 diabetes.Expert opinion on therapeutic targets · 2022
    Review
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

22 authors at 1 institution in 1 country.

Ella FungBioMedicine Design, Pfizer Inc., 610 N Main Street, Cambridge, MA, USA.
Liya KangInternal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA.
Diana SapashnikBioMedicine Design, Pfizer Inc., 610 N Main Street, Cambridge, MA, USA.
Susan BenardBioMedicine Design, Pfizer Inc., 610 N Main Street, Cambridge, MA, USA.
Annette SieversBioMedicine Design, Pfizer Inc., 610 N Main Street, Cambridge, MA, USA.
Yan LiuBioMedicine Design, Pfizer Inc., 610 N Main Street, Cambridge, MA, USA.
Guoying YanBioMedicine Design, Pfizer Inc., 610 N Main Street, Cambridge, MA, USA.
Jing ZhouBioMedicine Design, Pfizer Inc., 610 N Main Street, Cambridge, MA, USA.
Linette RodriguezBioMedicine Design, Pfizer Inc., 610 N Main Street, Cambridge, MA, USA.
Weijun MaBioMedicine Design, Pfizer Inc., 610 N Main Street, Cambridge, MA, USA.
Wayne R StochajBioMedicine Design, Pfizer Inc., 610 N Main Street, Cambridge, MA, USA.
Edward LaVallieBioMedicine Design, Pfizer Inc., 610 N Main Street, Cambridge, MA, USA.
Liliana WroblewskaBioMedicine Design, Pfizer Inc., 610 N Main Street, Cambridge, MA, USA.
Kerry KelleherBioMedicine Design, Pfizer Inc., 610 N Main Street, Cambridge, MA, USA.
Amy TamBioMedicine Design, Pfizer Inc., 610 N Main Street, Cambridge, MA, USA.
Olivier BezyInternal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA.
Danna BreenInternal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA.
Jeffrey R ChabotBioMedicine Design, Pfizer Inc., 610 N Main Street, Cambridge, MA, USA.
Tao HeBioMedicine Design, Pfizer Inc., 610 N Main Street, Cambridge, MA, USA.
Laura LinBioMedicine Design, Pfizer Inc., 610 N Main Street, Cambridge, MA, USA.
Zhidan WuInternal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA.
Lidia MosyakBioMedicine Design, Pfizer Inc., 610 N Main Street, Cambridge, MA, USA. Lidia.Mosyak@pfizer.com.
Pfizer (United States) · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

GDF15 is a distant TGF-β family member that induces anorexia and weight loss. Due to its function, GDF15 has attracted attention as a potential therapeutic for the treatment of obesity and its associated metabolic diseases. However, the pharmacokinetic and physicochemical properties of GDF15 present several challenges for its development as a therapeutic, including a short half-life, high aggregation propensity, and protease susceptibility in serum. Here, we report the design, characterization and optimization of GDF15 in an Fc-fusion protein format with improved therapeutic properties. Using a structure-based engineering approach, we combined knob-into-hole Fc technology and N-linked glycosylation site mutagenesis for half-life extension, improved solubility and protease resistance. In addition, we identified a set of mutations at the receptor binding site of GDF15 that show increased GFRAL binding affinity and led to significant half-life extension. We also identified a single point mutation that increases p-ERK signaling activity and results in improved weight loss efficacy in vivo. Taken together, our findings allowed us to develop GDF15 in a new therapeutic format that demonstrates better efficacy and potential for improved manufacturability.

Indexed as

AnimalsCHO CellsCricetulusGlial Cell Line-Derived Neurotrophic Factor ReceptorsGlycosylationGrowth Differentiation Factor 15HumansImmunoglobulin Fc FragmentsMicePoint MutationProtein EngineeringRecombinant Fusion ProteinsWeight LossGDF15 protein, humanGFRAL protein, mouseGlial Cell Line-Derived Neurotrophic Factor ReceptorsGrowth Differentiation Factor 15Immunoglobulin Fc FragmentsRecombinant Fusion Proteins

Identifiers

PMID33903632
PMCPMC8076310
OpenAlexW3158611749

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

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.