2:32 PM
Mar 14, 2019
 |  BC Extra  |  Preclinical News

Antibody-drug conjugate against ALK could selectively treat neuroblastoma

Researchers from CHOP and Celldex showed that an antibody-drug conjugate targeting ALK selectively kills neuroblastoma cells, suggesting the ADC could have a better safety profile than marketed drug dinutuximab.

Unituxin dinutuximab from United Therapeutics Corp. (NASDAQ:UTHR) and Qarziba dinutuximab beta from EUSA Pharma Ltd. (Hemel Hempstead, U.K.) are approved to treat pediatric patients with high-risk neuroblastoma. However, these anti-GD2 mAbs can lead to side effects including anaphylaxis and neurotoxicity, with relapse occurring in half of patients.

Previous studies showed that ALK is widely expressed on neuroblastoma cells, suggesting the gene could be targeted to treat the pediatric cancer. While small molecule ALK inhibitors are already marketed to treat other cancers, ALK protein mutations can lead to resistance against those drugs.

In a paper published in Science Translational Medicine, scientists from Children's Hospital of Philadelphia and Celldex Therapeutics Inc. (NASDAQ:CLDX) confirmed wild-type and mutated ALK expression in human-derived neuroblastoma cell lines and neuroblastoma patient-derived xenograft models, but found no expression in healthy tissue.

The scientists showed an ADC consisting of anti-ALK mAb CDX-0125 linked to chemotherapy drug thienoindole (TEI), known as CDX-0125-TEI, decreased cell viability in four human-derived neuroblastoma cell lines compared with control IgG1 conjugated to TEI.

In xenograft mouse models of neuroblastoma with either wild-type or mutant ALK, CDX-0125-TEI decreased tumor volume and increased survival compared with no treatment or CDX-0125 alone. The authors reported no treatment-induced toxicity.

Celldex has an exclusive license from CHOP to IP covering the use of ALK antibodies to inhibit neuroblastoma.

According to BioCentury's BCIQ database, there are no products in development to treat ALK-positive neuroblastoma.

Targets: ALK - Anaplastic lymphoma kinase; GD2 - Ganglioside GD2

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