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Updated: Jan 14, 2026
Non-Viral Engineering of Primary Human T Cells via Homology-Mediated End-Joining Targeted Integration of Large DNA Templates
Published on: May 9, 2025
Fully human targeted cytotoxic fusion proteins: new anticancer agents on the horizon
Ulrich H Weidle1, Guy Georges, Ulrich Brinkmann
1Roche Pharma Research and Early Development (pRED), Roche Diagnostics GmbH, Im Nonnenwald 2, D-82377 Penberg, Germany. ulrich.weidle@roche.com
Abstract:
Cytotoxic fusion proteins for tumor therapy are composed of an antibody-based targeting moiety and an effector molecule. Effectors may possess enzymatic activity confering cytoxicity after internalization or be an antibody-targeted death-receptor ligand that induces apoptosis after interaction with a death receptor. In this review, we focus on cytotoxic fusion proteins which, in most cases, are composed of fully human targeting and effector moieties. Regarding the first category, as outlined above, we focus on fusion proteins based on ribonucleases, granzyme B, apoptosis-inducing factor and death-associated protein kinases. The second category of fusion proteins makes use of cell-death inducing ligands such as tumor-necrosis factor, tumor necrosis factor α-related, apoptosis-inducing ligand fas ligand and a tumor-targeting antibody moiety. For the latter category, prodrug-related concepts are also covered. The critical issues to be resolved for improved efficacy and safety are discussed.
Insights
This review explores cytotoxic fusion proteins for cancer treatment, detailing antibody-based therapies with enzymatic or death-receptor ligand effectors. Critical issues for enhancing efficacy and safety are discussed.
Area of Science:
- Oncology
- Immunotherapy
- Biotechnology
Background:
- Cytotoxic fusion proteins combine antibody targeting with effector molecules for tumor therapy.
- Effectors can be enzymes causing cytotoxicity or death-receptor ligands inducing apoptosis.
Purpose of the Study:
- To review cytotoxic fusion proteins, focusing on fully human targeting and effector moieties.
- To discuss fusion proteins utilizing enzymatic effectors (ribonucleases, granzyme B) and death-receptor ligands (TNF, FasL).
- To cover prodrug concepts and critical issues for improved efficacy and safety.
Main Methods:
- Literature review of cytotoxic fusion proteins in cancer therapy.
- Categorization of fusion proteins based on effector mechanisms (enzymatic vs. ligand-induced).
- Analysis of antibody-based targeting moieties and effector molecules.
Main Results:
- Two main categories of cytotoxic fusion proteins identified: enzymatic and death-receptor ligand-based.
- Focus on fully human components for enhanced therapeutic potential.
- Prodrug strategies are also relevant for ligand-based fusion proteins.
Conclusions:
- Cytotoxic fusion proteins offer promising avenues for tumor therapy.
- Further research is needed to address critical issues for improved efficacy and safety.
- Development of fully human fusion proteins is a key trend.
