EACR25-1836

Oncofetal Chondroitin Sulfate represents a Target for Antibody Drug-Conjugate therapy of Acute Myeloid Leukemia

J. Mujollari¹, M. Estruch^2,3, P. Khadgawat^2,3, S. Choudhary^1,4, T. Gustavsson^1,4, E. Vidal-Calvo¹, A. Tølbøll Sørensen⁵, M. Agerbæk^1,6, A. Salanti^1,4, K. Theilgaard-Mönch^2,3

¹Centre for translational Medicine and Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
²Biotech Research and Innovation Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
³The Finsen Laboratory, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
⁴VAR2 Pharmaceuticals ApS, Frederiksberg, Denmark
⁵Department of Hematology, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
⁶VarCT Diagnostics, Frederiksberg, Denmark

Introduction:

Acute Myeloid Leukemia (AML) is a highly aggressive hematological malignancy with poor clinical outcome due to resistance or early relapse after treatment with current standard therapies. Despite recent therapeutic advancements, there remains an unmet need for novel, targeted strategies. Oncofetal chondroitin sulfate (ofCS) is a promising new cancer target due to its high expression on many cancer entities and low expression on healthy tissues. Our previous studies have demonstrated the potent anti-tumor efficacy of anti-ofCS antibody drug-conjugates (ADC) in solid tumor models. Here, we explore the therapeutic potential of an anti-ofCS ADC in AML.

Material and method:

Cell surface expressed ofCS was analyzed in bone marrow (BM) samples from AML patients and healthy donors using flow cytometry. The cytotoxic effect of anti-ofCS ADC was assessed in vitro drug-killing assays utilizing four AML cell lines. Additionally, in vivo efficacy was evaluated in two AML patient-derived xenograft (PDX) models, established from bio-banked AML patient BM samples.

Result and discussion:

Flow cytometry analyses showed significantly higher ofCS levels on BM cells from AML patients and PDX compared to BM cells from healthy donors, which exhibited low or undetectable ofCS levels. Consistently, anti-ofCS ADC demonstrated effective in vitro killing of four ofCS+ AML cell lines. Furthermore, anti-ofCS ADC treatment led to significantly prolonged survival in two AML PDX models compared to a protein drug-conjugate control, with minimal adverse effects. Notably, endpoint analysis of AML PDXs demonstrated ofCS expression on human CD45+ AML cells following the anti-ofCS ADC treatment, indicating intrinsic maintenance of ofCS expression by AML cells independently of treatment. Collectively, our findings highlight the ability of anti-ofCS ADC to selectively target and eliminate AML cells both in vitro and in vivo in preclinical trials.

Conclusion:

This study provides the first evidence supporting ofCS as a specific and therapeutically relevant target for AML. Our results underscore the potential of anti-ofCS ADC as a promising new strategy for AML therapy, warranting future exploration in clinical trials.