Abstract 93P
Background
Osteosarcoma (OS) is a rare primary cancer of the bone characterised by its aggressive nature, strong invasiveness, rapid disease progression and high mortality rate. As patient outcomes have stagnated in the last 40 years, there remains a high unmet clinical need for novel targeted therapies to treat OS. Annexin-A1 (ANXA1), a 37 kDa phospholipid-binding protein, is overexpressed in several tumours, with high expression correlating with both poor patient outcomes and tumour growth and metastasis. Data from the St Jude-Washington University Children's Research Hospital Pediatric Cancer Genome Project (PCGP) identified a substantial fraction of OS with high ANXA1 expression suggesting it is a novel therapeutic target in OS. MDX-124 is a first-in-class humanised antibody targeting ANXA1 currently being evaluated in a phase I clinical trial (ATTAINMENT). Here we present data demonstrating efficacy of MDX-124 in preclinical OS models.
Methods
ANXA1 gene expression and protein levels in OS samples were assessed via RNA-seq and immunohistochemistry respectively. Imaging flow cytometry measured ANXA1 expression and cellular localisation in human OS cell lines. OS cell viability following incubation with MDX-124 alone or in combination with standard of care therapies (methotrexate, doxorubicin, cisplatin, ifosamide or etoposide) was assessed via MTT assay. The effect of MDX-124 on OS cell cycle progression was evaluated by measuring changes in DNA content using flow cytometry. A transwell assay was used to evaluate the impact of MDX-124 on OS cell migration.
Results
OS tissues and human OS cell lines displayed high levels of ANXA1 expression. Incubation of OS cell lines with MDX-124 significantly reduced cell growth via cell cycle arrest in a dose-dependent manner. MDX-124 also significantly reduced the migratory ability of OS cell lines and enhanced the anti-cancer activity of several standard of care OS therapies.
Conclusions
MDX-124 targets secreted ANXA1 preventing activation of FPR1/2 and reducing cancer progression. MDX-124 has demonstrated anti-tumour activity in several preclinical models of OS. Medannex plans to initiate a phase Ib study of MDX-124 in paediatric OS in late 2025.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Medannex Limited.
Funding
Medannex Limited.
Disclosure
F. Dempsey, S. Crichton: Financial Interests, Personal, Full or part-time Employment: Medannex Limited. C. Parris, R. Ibrahem, H. Al-Ali, C. Pepper: Financial Interests, Institutional, Research Grant: Medannex Limited. All other authors have declared no conflicts of interest.