Targeting tumor-selective membrane-associated PCNA enables selective antibody-drug conjugate therapy.
4 affiliations
- 1The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
- 2Institiute of Pathology, Barzilai University Medical Center, Ashkelon, Israel.
- 3llse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
- 4Blood Cell Development and Host Defense Program, Research Institute at Fox Chase Cancer Center, Philadelphia, PA, USA.
Abstract
Membrane-associated proliferating cell nuclear antigen (mPCNA) is an attractive tumor-selective antigen for antibody-drug conjugate (ADC) development. We generated a chimeric IgG1 ADC, RC14-MMAE, to exploit three key properties of mPCNA that support its use as an efficient delivery platform. First, flow-cytometric and imaging analyses show abundant mPCNA surface expression on multiple tumor cell lines and in JIMT1 xenografts, providing accessible epitopes for binding. Second, comparative profiling against non-malignant counterparts and normal mouse tissues reveals minimal or undetectable mPCNA at the plasma membrane of healthy cells, indicating a sharp tumor-normal differential expected to limit off-tumor targeting and improve the therapeutic window. Third, live-cell internalization assays demonstrate that RC14 rapidly accumulates in LAMP1-positive lysosomes after engaging mPCNA, confirming efficient trafficking along the endolysosomal pathway required for protease-mediated cleavage of the valine-citrulline linker and release of monomethyl auristatin E (MMAE). Consistent with this target profile, RC14-MMAE exhibits potent antigen-dependent cytotoxicity in mPCNA-positive tumor models in NSG mice, favorable pharmacokinetics, sustained payload retention in serum, robust in vivo antitumor activity with limited overt toxicity, and a significantly increased fraction of F4/80⁺ tumor-infiltrating myeloid cells within dissociated tumors. These findings establish mPCNA as a functionally validated, tumor-selective internalizing target and support RC14-MMAE as a first-in-class mPCNA-directed ADC with broad translational potential.
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BibTeX
@article{ahmad2026targeting,
title = {{Targeting tumor-selective membrane-associated PCNA enables selective antibody-drug conjugate therapy.}},
author = {Muhammad Abu Ahmad and Nir Miriam Ungar-Malma and Alon Naumchik and Noy Machluf-Katz and Olga Radinsky and Sarah Adi Eisdorfer and Abedallh Gara and Yosef Istoyler and Irit Alon and Daniel Sevilla-Sanchez and Kerry S Campbell and Bar Kaufman and Moshe Elkabets and Angel Porgador},
journal = {Oncoimmunology},
year = {2026},
month = oct,
doi = {10.1080/2162402x.2026.2740432},
url = {https://europepmc.org/article/MED/42873150},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Targeting tumor-selective membrane-associated PCNA enables selective antibody-drug conjugate therapy.
AU - Muhammad Abu Ahmad
AU - Nir Miriam Ungar-Malma
AU - Alon Naumchik
AU - Noy Machluf-Katz
AU - Olga Radinsky
AU - Sarah Adi Eisdorfer
AU - Abedallh Gara
AU - Yosef Istoyler
AU - Irit Alon
AU - Daniel Sevilla-Sanchez
AU - Kerry S Campbell
AU - Bar Kaufman
AU - Moshe Elkabets
AU - Angel Porgador
PY - 2026
DA - 2026/10/14
JO - Oncoimmunology
DO - 10.1080/2162402x.2026.2740432
UR - https://europepmc.org/article/MED/42873150
AB - Membrane-associated proliferating cell nuclear antigen (mPCNA) is an attractive tumor-selective antigen for antibody-drug conjugate (ADC) development. We generated a chimeric IgG1 ADC, RC14-MMAE, to exploit three key properties of mPCNA that support its use as an efficient delivery platform. First, flow-cytometric and imaging analyses show abundant mPCNA surface expression on multiple tumor cell lines and in JIMT1 xenografts, providing accessible epitopes for binding. Second, comparative profiling against non-malignant counterparts and normal mouse tissues reveals minimal or undetectable mPCNA at the plasma membrane of healthy cells, indicating a sharp tumor-normal differential expected to limit off-tumor targeting and improve the therapeutic window. Third, live-cell internalization assays demonstrate that RC14 rapidly accumulates in LAMP1-positive lysosomes after engaging mPCNA, confirming efficient trafficking along the endolysosomal pathway required for protease-mediated cleavage of the valine-citrulline linker and release of monomethyl auristatin E (MMAE). Consistent with this target profile, RC14-MMAE exhibits potent antigen-dependent cytotoxicity in mPCNA-positive tumor models in NSG mice, favorable pharmacokinetics, sustained payload retention in serum, robust in vivo antitumor activity with limited overt toxicity, and a significantly increased fraction of F4/80⁺ tumor-infiltrating myeloid cells within dissociated tumors. These findings establish mPCNA as a functionally validated, tumor-selective internalizing target and support RC14-MMAE as a first-in-class mPCNA-directed ADC with broad translational potential.
SN - 2162-4011
SN - 2162-402X
ER -