Highlights
- Oncofetal chondroitin sulfate (ofCS) is highly expressed in AML blasts and patient-derived xenografts (PDXs) but largely absent in healthy adult bone marrow and hematopoietic stem cells.
- Anti-ofCS antibodies demonstrate rapid internalization,
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a prerequisite for effective delivery of cytotoxic payloads via antibody-drug conjugates (ADCs). - In preclinical PDX models, anti-ofCS ADCs significantly prolonged survival with a favorable safety profile, avoiding the severe hematotoxicity typical of CD33- or CD123-targeted therapies.
- This study identifies glycosaminoglycans as a new class of druggable targets in hematologic malignancies, potentially expanding treatment options for older or unfit patients.
Background
Acute myeloid leukemia (AML) remains a therapeutic challenge, characterized by high rates of relapse and significant treatment-related morbidity. The advent of antibody-drug conjugates (ADCs) promised a new era of precision oncology, yet clinical success has been tempered by the lack of truly leukemia-specific antigens. Most current targets, such as CD33 (targeted by gemtuzumab ozogamicin) and CD123, are also expressed on healthy hematopoietic stem cells (HSCs) and myeloid progenitors. This shared expression leads to profound and prolonged myelosuppression, which limits the therapeutic window and frequently excludes older patients or those with multiple comorbidities from receiving these potentially life-saving agents.
To overcome these limitations, researchers have looked beyond protein antigens to the complex carbohydrate structures on the cell surface. Oncofetal chondroitin sulfate (ofCS) is a specific glycosaminoglycan modification originally identified in the placenta. While vital for fetal development, its expression in adult tissues is restricted to certain malignant transformations. Previous studies have localized ofCS on a variety of solid tumors, where it facilitates invasion and signaling, but its role and therapeutic potential in leukemia have remained unexplored until now.
Key Content
A Novel Glycan Target in the Bone Marrow Niche
The study by Mujollari et al. (2026) utilized primary bone marrow samples from AML patients and healthy donors to map the landscape of ofCS expression. Using high-affinity recombinant proteins and antibodies specifically designed to recognize the ofCS modification, the investigators demonstrated a striking disparity in expression levels. AML bone marrow cells and patient-derived xenograft (PDX) cells showed high levels of ofCS. In contrast, bone marrow cells from healthy individuals exhibited low to undetectable levels of this glycan. This high degree of tumor-specificity is rare in AML, where most protein markers are present to some degree on healthy hematopoietic precursors.
Internalization and Mechanism of Action
For an ADC to be effective, the target antigen must not only be specific but also capable of internalizing the antibody-linker-payload complex into the endosomal-lysosomal compartment. Mujollari et al. confirmed that anti-ofCS antibodies bind to AML cells and are rapidly internalized. Upon internalizing the anti-ofCS ADCs, the leukemia cells underwent targeted apoptosis in vitro. The specificity of the killing was further validated by the lack of toxicity observed in healthy hematopoietic progenitor assays, highlighting a significantly wider therapeutic window than that of current protein-targeted ADCs.
Preclinical Efficacy in PDX Models
The translational potential of anti-ofCS ADCs was most clearly demonstrated in vivo. Using AML PDX models—the gold standard for mimicking human disease complexity—the researchers treated mice with anti-ofCS ADCs. The results were statistically significant: treated mice showed a substantial prolongation of overall survival compared to control groups. Crucially, the anti-leukemic effect was achieved without the systemic toxicity or severe marrow depletion that often complicates preclinical testing of myeloid-targeted agents. These findings suggest that targeting ofCS can effectively clear the leukemic burden while sparing the healthy marrow infrastructure.
Expert Commentary
The discovery of ofCS as a druggable target in AML marks a pivotal shift in how we approach antigen discovery. Traditionally, the field has focused on the proteome; however, this study underscores that the “glycome” may hold the key to overcoming off-target toxicities. From a clinical perspective, the most exciting aspect of anti-ofCS ADCs is their potential application in patients who are ineligible for intensive induction chemotherapy.
However, several questions remain before clinical implementation. The heterogeneity of ofCS expression across different AML molecular subtypes (e.g., FLT3-ITD, NPM1 mutations, or complex karyotypes) needs further characterization to determine which patient populations will benefit most. Additionally, as with all ADCs, the stability of the linker and the choice of payload (e.g., auristatins vs. PBD dimers) will be critical in determining the final safety profile in humans. The fact that ofCS is also expressed in many solid tumors suggests that this ADC platform could have broad utility across oncology, potentially reducing the costs of development through multi-indication applications.
Conclusion
The study by Mujollari et al. provides the first evidence that oncofetal chondroitin sulfate is a highly specific and potent target for ADC therapy in acute myeloid leukemia. By exploiting the unique glycan signature of malignant cells, this approach sidesteps the hematotoxicity that has plagued previous targeted therapies. As we move toward first-in-human trials, ofCS-targeted ADCs represent a promising new frontier for achieving durable remissions in AML with a manageable safety profile, offering hope for a broader range of patients than ever before.
References
- Mujollari J, Estruch M, Khadgawat P, et al. The glycosaminoglycan oncofetal chondroitin sulfate is a novel target for antibody-drug conjugate therapy for AML. Blood. 2026;147(11):1229-1236. PMID: 41405498.
- Salanti A, Clausen TM, Agerbæk MØ, et al. Targeting Chondroitin Sulfate Glycans to Inhibit Solid Tumor Growth and Metastasis. Cancer Cell. 2015;28(4):500-514. (Contextual reference for ofCS in cancer).