Evidence map›Paper›PMID 40713730›Full record

ArticleAlzheimer's research & therapy2025

Development of AL101 (GSK4527226), a progranulin-elevating monoclonal antibody, as a potential treatment for Alzheimer's disease.

Balasubrahmanyam Budda, Ananya Mitra, Lovingly Park, Hua Long, Michael Kurnellas, Nga Bien-Ly, William Estacio, Brady Burgess, Grace Chao, Tina Schwabe and 3 more

Registry-linked trialAbstract readClinical Trial, Phase I
PubMed Full text at PMC Publisher
In one paragraph

Article in Alzheimer's research & therapy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04111666 (A Phase 1 Study in Healthy Volunteers to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Bioavailability of IV and SC AL101), which is not on this map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing 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.

NCT04111666 phase1completednot on this map

A Phase 1 Study in Healthy Volunteers to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Bioavailability of IV and SC AL101

TypeinterventionalSponsorAlector Inc.Ran2019 to 2022Enrolled88ConditionsHealthyArmsAL101, Placebo
3 · Its place in the literature

Who cites it

5 citing papers in PubMed.

  1. Article
  2. Review
  3. Article
  4. Review
  5. 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

13 authors.

Balasubrahmanyam Budda *Alector, Inc, 131 Oyster Point Blvd, #600, South San Francisco, CA, 94080, USA. balasubrahmanya.budda@alector.com.
Ananya Mitra *Alector, Inc, 131 Oyster Point Blvd, #600, South San Francisco, CA, 94080, USA.
Lovingly Park *Alector, Inc, 131 Oyster Point Blvd, #600, South San Francisco, CA, 94080, USA.
Hua LongAlector, Inc, 131 Oyster Point Blvd, #600, South San Francisco, CA, 94080, USA.
Michael KurnellasNeuron23, South San Francisco, CA, 94080, USA.
Nga Bien-LyAlector, Inc, 131 Oyster Point Blvd, #600, South San Francisco, CA, 94080, USA.
William EstacioDeep Apple Therapeutics, South San Francisco, CA, 94080, USA.
Brady BurgessAlector, Inc, 131 Oyster Point Blvd, #600, South San Francisco, CA, 94080, USA.
Grace ChaoAlector, Inc, 131 Oyster Point Blvd, #600, South San Francisco, CA, 94080, USA.
Tina SchwabeNine Square Therapeutics, Inc, South San Francisco, CA, 94080, USA.
Robert PaulNine Square Therapeutics, Inc, South San Francisco, CA, 94080, USA.
Sara Kenkare-MitraAlector, Inc, 131 Oyster Point Blvd, #600, South San Francisco, CA, 94080, USA.
Arnon RosenthalAlector, Inc, 131 Oyster Point Blvd, #600, South San Francisco, CA, 94080, USA.

Funding

SORT1:PGRN blocking antibodies for Frontotemporal dementiaR44AG050363 · NIA · ALECTOR, LLC · PI ROSENTHAL, ARNON · 2015 to 2016
$1.5M
NIA NIH HHS R44 AG050363NIH HHS R44AG050363
6 · The paper itself

Abstract

backgroundAlzheimer's disease (AD) is characterized by amyloid plaques, tau tangles, and neuronal loss. Progranulin (PGRN) is a secreted immune regulator, lysosomal chaperone, and neuronal survival factor. Genetic polymorphisms that reduce PGRN levels are associated with an increased risk for AD and other neurodegenerative disorders. The receptor sortilin binds and targets PGRN for lysosomal degradation, resulting in a reduction of extracellular PGRN. AL101 (GSK4527226) is a monoclonal antibody that binds to the sortilin receptor and is being developed as a potential PGRN-elevating therapy for AD.

methodsCell-based in vitro studies examined the interaction of AL101 with sortilin and its effect on PGRN levels. In vivo studies evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of AL101 in rats and nonhuman primates. A phase 1 study in healthy volunteers assessed PK, safety, tolerability, and PD biomarkers after intravenous or subcutaneous dosing of AL101.

resultsCell-based assays showed that AL101 increased PGRN levels by decreasing cell surface sortilin levels and partially blocking the sortilin-PGRN interaction. Preclinical studies in rats and monkeys demonstrated that AL101 decreased cell surface sortilin levels on white blood cells and increased PGRN levels by up to 2-fold in cerebrospinal fluid (CSF) and up to 4-fold in blood. In the phase 1 study in healthy volunteers, both single and multiple doses of AL101 led to significant increases in plasma and CSF PGRN levels, providing additional support for its potential as a PGRN-elevating therapy. LIMITATIONS: The first-in-human dose-finding study was aimed at investigating the safety and tolerability of AL101 and was not sufficiently powered to detect changes in exploratory outcomes, such as neurodegeneration biomarkers. Clinical studies are needed to evaluate AL101 in AD patients.

conclusionsAL101 was shown to bind sortilin and decrease cell surface sortilin levels, leading to consistent elevations of PGRN across in vitro, preclinical, and human studies. These results support continued development of AL101 and its investigation as a potential treatment for AD and other neurodegenerative conditions where PGRN could play a role.

trial registrationClinicaltrials.gov, NCT04111666. Registered on October 1, 2019. https://clinicaltrials.gov/ct2/show/NCT04111666 .

Indexed as

Alzheimer DiseaseAntibodies, MonoclonalProgranulinsAdaptor Proteins, Vesicular TransportAnimalsFemaleHumansMaleRatsRats, Sprague-DawleySortilinAdaptor Proteins, Vesicular TransportAntibodies, MonoclonalGRN protein, humanProgranulinsSortilinAL101Alzheimer’s diseaseClinical trialMonoclonal antibodyNeurodegenerative diseasesProgranulinSortilin

Identifiers

PMID40713730
PMCPMC12291526

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Registered trials

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.