Evidence map›Paper›PMID 40661577›Full record

ArticlebioRxiv : the preprint server for biology2025

Low-density lipoprotein receptor-targeting chimeras for membrane protein degradation and enhanced drug delivery.

Fangzhu Zhao, Yan Wu, Kaitlin Schaefer, Yun Zhang, Kun Miao, Zi Yao, Snehal D Ganjave, Kaan Kumru, Trenton M Peters-Clarke, Alex Inague and 3 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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

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

0 citing papers in PubMed.

No citing paper in PubMed yet.

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.

Fangzhu ZhaoDepartment of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.ORCID 0000-0002-3172-1340
Yan WuDepartment of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
Kaitlin SchaeferDepartment of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
Yun ZhangDepartment of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
Kun MiaoDepartment of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
Zi YaoDepartment of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
Snehal D GanjaveDepartment of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
Kaan KumruDepartment of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
Trenton M Peters-ClarkeDepartment of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
Alex InagueDepartment of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA, USA.
James A OlzmannDepartment of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA, USA.ORCID 0000-0001-7751-8316
Kevin K LeungDepartment of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.ORCID 0000-0002-2087-4974
James A WellsDepartment of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.

Funding

Surfaceomic technologies and antibodies to probe cell surface proteomes and their interactomes at unprecedented small scale and high-resolutionR35GM122451 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI JAMES A WELLS · 2017 to 2026
$5.3M
MYCN drives a ferroptotic vulnerability in neuroblastomaR01CA276207 · NCI · VIRGINIA COMMONWEALTH UNIVERSITY · PI Anthony Charles Faber, JAMES A OLZMANN · 2023 to 2026
$2.9M
New protein engineering-based tools and technologies for characterizing cell surface proteolysis in cancer cells for novel neo-epitope biomarkers and drug targetsR01CA248323 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI JAMES A WELLS · 2020 to 2026
$2.6M
NCI NIH HHS R01 CA248323NCI NIH HHS R01 CA276207NIGMS NIH HHS R35 GM122451
6 · The paper itself

Abstract

Antibody-based therapeutics encompass diverse modalities for targeting tumor cells. Among these, antibody-drug conjugates (ADCs) and extracellular targeted protein degradation (eTPD) specifically depend on efficient lysosomal trafficking for activity. However, many tumor antigens exhibit poor internalization, limiting ADC effectiveness. To address this, we developed low-density lipoprotein receptor-targeting chimeras (LIPTACs), leveraging the constitutive endocytic and recycling activity of the LDLR to enhance lysosomal delivery. LIPTACs enable efficient and selective degradation of diverse extracellular membrane proteins. Additionally, by coupling LIPTACs with cytotoxic payloads to generate degrader-drug conjugates, we can achieve superior intracellular delivery and enhanced cytotoxicity compared to conventional ADCs. The dual modality addresses key challenges of inadequate internalization in conventional ADCs and cytotoxic potency for current eTPD strategies. Our findings demonstrate that LDLR-mediated trafficking can enhance eTPD and ADCs, providing a hybrid blueprint for developing next-generation antibody therapeutics with broader utility and improved efficacy in cancer treatment.

Identifiers

PMID40661577
PMCPMC12258987

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.