Mechanistic modeling suggests stroma-targeting antibody-drug conjugates as an alternative to cancer-targeting in cases of heterogeneous target exspression
N. Ezgi Wood, Anıl Cengiz, Ming Gao, Alexander V. Ratushny, Ronny Straube
Abstract
Antibody-drug conjugates (ADCs) are gaining increasing traction in the treatment of oncological diseases; however, many clinical failures have also been observed. One key factor limiting ADC effectiveness is the heterogeneous expression of their target antigen. While the vast majority of ADCs in clinical development target antigens on cancer cells (cancer-targeting), they can also target antigens expressed on non-cancerous stromal cells in the tumor microenvironment (stroma-targeting). It remains unclear if ADCs targeting stromal cells can outperform cancer-targeting ADCs.
Introduction
Antibody-drug conjugates (ADCs) are therapeutic agents composed of three main components: an antibody, a payload, and a linker that connects the two. This combination enables ADCs to leverage the specificity of antibodies for targeting and potency of the payloads to kill the target cells [1]. Upon binding to their targets on the cell surface, ADCs are internalized, and the payload is released inside the cells. The payload can then diffuse out of the target cells into neighboring cells and kill them, a phenomenon known as bystander killing. This mechanism allows ADCs to eliminate antigen-negative (Ag-) cells in the tumor microenvironment (TME) as well (Fig 1A) [2].
Materials and method
Overview of mathematical models
Here, we present three related ordinary differential equation (ODE) models describing the mechanism of action of ADCs in various scenarios. The first model is the One-Cell Type Model, which incorporates only Ag+ cells in the Tumor compartment, representing Ag+ cancer cells. This model simulates a cancer-targeting ADC aimed at a tumor with homogenous target expression in the cancer cells (Figs 1B and S1).
Results
Cancer-targeting ADCs may provide limited durability of response when the target antigen is expressed heterogeneously, whereas stroma-targeting ADCs may overcome this limitation
Here, we simulate 5.4 mg/kg Q3W ADC treatment schedule. This treatment regimen leads to tumor regression with the One-Cell Type Model (Figs 2A and S3A).
Discussion
In this study, we present novel models to assess ADC efficacy across various scenarios, providing key insights into ADC mechanism of action and potential limitations of this modality. Our simulations indicate that cancer-targeting ADCs may not provide durable responses when their target antigen is heterogeneously expressed. Specifically, ADCs cause higher internal payload levels in Ag+ cells than Ag- cells.
Acknowledgments
We gratefully thank Anna Kondic for providing feedback on the manuscript.
Citation: Wood NE, Cengiz A, Gao M, Ratushny AV, Straube R (2025) Mechanistic modeling suggests stroma-targeting antibody-drug conjugates as an alternative to cancer-targeting in cases of heterogeneous target exspression. PLoS Comput Biol 21(8): e1012839. https://doi.org/10.1371/journal.pcbi.1012839
Editor: Marc R. Birtwistle,, Clemson University, UNITED STATES OF AMERICA
Received: January 30, 2025; Accepted: July 23, 2025; Published: August 13, 2025
Copyright: © 2025 Wood et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: NEW, AC, MG, AVR, and RS are funded by Bristol Myers Squibb. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: NEW, MG, AVR are current BMS employees and own BMS stock. RS is a former BMS employee. AC was a BMS summer intern.
