In a groundbreaking development that could reshape the landscape of cancer immunotherapy, researchers from Singapore’s ASTAR Institute of Molecular and Cell Biology (IMCB) in collaboration with biotechnology company Intra-ImmuSG have unveiled promising results from a Phase II clinical trial of PRL3-zumab, a novel humanized antibody therapy. Detailed in the prestigious journal Cell Reports Medicine*, the trial demonstrated that PRL3-zumab safely and effectively delays disease progression in patients afflicted with advanced solid tumors that have proven resistant to current treatment modalities. This innovative therapy paves the way for a new treatment paradigm, particularly for patients with aggressive cancers that have exhausted conventional options.
Traditionally, antibody therapies have targeted extracellular or cell surface proteins due to the accessibility of these sites. However, PRL3-zumab breaks this convention by targeting PRL3, an intracellular enzyme with high expression in approximately 80% of solid tumors, yet undetectable in healthy tissues. The remarkable novelty lies in PRL3-zumab’s ability to recognize transient expression of PRL3 on the surface of cancer cells—a phenomenon that was previously underappreciated—thereby enabling the immune system to specifically identify and eradicate malignant cells via mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis. This strategy circumvents a longstanding challenge in targeted cancer therapies: the "undruggable" nature of intracellular oncoproteins.
The Phase II multicenter trial enrolled 51 participants diagnosed with various advanced-stage solid tumors refractory to standard treatments, including conventional immunotherapies. Patients treated with PRL3-zumab showed a median progression-free survival substantially longer than historical controls. Notably, one patient with Stage IV gastric cancer achieved disease stabilization lasting over 13 months, a significant extension compared to the typical two months progression seen with existing therapies in similar cohorts. This clinical evidence positions PRL3-zumab as a potential rescue therapy for a population with very limited therapeutic options.
Beyond simply halting disease progression, preliminary data emerging from concurrent trials in Malaysia and China have revealed encouraging signs of tumor regression, suggesting that PRL3-zumab may not only contain but actively reduce tumor burden. While final evaluations from these ongoing international studies are under analysis, the initial findings signify a broader efficacy spectrum for PRL3-zumab across different populations and tumor types. The convergence of these global efforts underscores the growing enthusiasm around this novel intervention.
The scientific underpinning of PRL3-zumab’s development traces back to Professor Qi Zeng from ASTAR IMCB, who first identified PRL3 in 1998, uncovering its pivotal role in cancer metastasis and therapeutic resistance. His pioneering work illuminated PRL3 as a crucial driver of tumor aggressiveness, inspiring efforts to design a targeted antibody approach. This research milestone catalyzed the formation of Intra-ImmuSG, an ASTAR spin-off dedicated to translating laboratory discoveries into tangible clinical innovations, exemplifying a successful bench-to-bedside enterprise.
A distinctive feature of the clinical trial was its employment of the Single Evaluable Patient Single Cohort (SEPSC) design, an innovative methodological approach allowing for rigorous intra-patient comparisons. By contrasting each patient’s progression-free survival while on PRL3-zumab against their own historical treatment responses and established benchmarks, the trial design enhanced the precision and validity of efficacy assessments in a challenging, heterogeneous patient population. This analytical novelty complements the biological innovation embodied by PRL3-zumab.
Safety remains a fundamental concern in cancer therapeutics, especially for novel agents. Reassuringly, the trial reported no serious drug-related adverse events, attesting to PRL3-zumab’s favorable safety profile. Such tolerability is critical for patients with limited treatment options who often face high toxicity burdens from conventional chemotherapy or immunotherapy. The well-tolerated nature of this therapy supports its potential integration into existing treatment regimens and provides rationale for further clinical evaluation.
The conceptual leap achieved by targeting intracellular proteins with monoclonal antibodies challenges long-held dogma about druggable targets in oncology. Historically, intracellular oncoproteins were considered inaccessible to antibody-based therapies due to their localization behind the cell membrane. PRL3-zumab’s success demonstrates that intracellular antigens, when transiently presented on the cell surface, can be exploited therapeutically, thereby opening new frontiers for antibody engineering and immunotherapy. This innovative approach has broad implications for targeting a plethora of intracellular cancer drivers previously deemed undruggable.
Beyond its immediate clinical impact, PRL3-zumab symbolizes a transformation in cancer treatment philosophy—shifting from targeting surface markers alone to embracing the dynamic biology of tumor cells, including intracellular processes. This could lead to the development of a new class of immunotherapies directed at intracellular pathways, significantly enlarging the repertoire of actionable cancer targets and providing hope for patients with rare, aggressive malignancies lacking effective treatment options.
Professor Qi Zeng, reflecting on this milestone, emphasized the significance of PRL3-zumab as a testament to translational science’s power: “This research product has already benefited many late-stage cancer patients and offers new hope to those with rare, aggressive cancers, helping to extend both survival and quality of life in patients who had run out of options.” His vision encompasses expanding PRL3-zumab’s utility and continuing to innovate in the immune-oncology space.
Looking ahead, the full data from ongoing Phase II studies in multiple Asian countries are anticipated to further elucidate PRL3-zumab’s therapeutic potential. Researchers remain optimistic that these investigations will provide comprehensive evidence supporting regulatory approvals and clinical adoption. With the global oncology community closely monitoring these developments, PRL3-zumab may herald a new era of targeted immunotherapy for solid tumors.
The collaborative effort between A*STAR IMCB’s academic expertise and Intra-ImmuSG’s translational research capabilities exemplifies the synergy required to accelerate novel cancer treatments from conception to patient care. This partnership not only enables rapid clinical progress but also reinforces Singapore’s position as a hub for cutting-edge biomedical innovation, fostering breakthroughs that resonate worldwide.
In summary, PRL3-zumab represents a revolutionary advance in cancer immunotherapy by successfully targeting an intracellular oncoprotein with a humanized antibody. The Phase II trial results provide compelling evidence of its safety and efficacy in a difficult-to-treat patient population, with encouraging signs of durable disease control and tumor regression. By leveraging a unique biological mechanism and pioneering clinical trial design, PRL3-zumab may open new pathways for the treatment of solid tumors, offering hope to patients burdened by refractory malignancies.
Subject of Research: PRL3-zumab, a novel cancer immunotherapy targeting intracellular PRL3 in advanced solid tumors.
Article Title: The PRL3-zumab paradigm: A multicenter, single-dose-level phase 2 basket clinical trial design of an unconventional cancer immunotherapy.
News Publication Date: 8 May 2025
Web References:
- Cell Reports Medicine article: https://www.cell.com/cell-reports-medicine/pdfExtended/S2666-3791(25)00193-4
- A*STAR IMCB website: http://www.a-star.edu.sg/imcb
- Intra-ImmuSG website: https://www.intra-immusg.com
References:
Park, D.J., Thura, M., Chiu, V.K. et al. The PRL3-zumab paradigm: A multicenter, single-dose-level phase 2 basket clinical trial design of an unconventional cancer immunotherapy. Cell Reports Medicine (2025).
Keywords: Biomedical engineering, cancer immunotherapy, PRL3-zumab, intracellular oncoproteins, antibody-dependent cellular cytotoxicity, translational research, clinical oncology, drug development.
