An antibody-drug conjugate directed to the ALK receptor demonstrates efficacy in preclinical models of neuroblastoma
Menée in vitro et à l'aide de modèles murins de neuroblastome, cette étude met en évidence l'efficacité thérapeutique d'un conjugué anticorps-médicament ciblant le récepteur ALK
Anaplastic lymphoma kinase (ALK) is frequently expressed in neuroblastoma, one of the more common pediatric cancers. Although small-molecule inhibitors of ALK are already in clinical use, the target protein often develops mutations that impede the effectiveness of these drugs. As an alternative to chemical inhibitors, Sano et al. developed an antibody-drug conjugate consisting of an antibody that recognizes ALK and a toxin that kills the ALK-expressing cells. The authors confirmed that ALK is not expressed in normal healthy tissues, indicating that this approach should be safe, and demonstrated the efficacy of the antibody-drug conjugate in mouse models of neuroblastoma with wild-type and mutant ALK.Enthusiasm for the use of antibody-drug conjugates (ADCs) in cancer therapy has risen over the past few years. The success of this therapeutic approach relies on the identification of cell surface antigens that are widely and selectively expressed on tumor cells. Studies have shown that native ALK protein is expressed on the surface of most neuroblastoma cells, providing an opportunity for development of immune-targeting strategies. Clinically relevant antibodies for this target have not yet been developed. Here, we describe the development of an ALK-ADC, CDX-0125-TEI, which selectively targets both wild-type and mutated ALK-expressing neuroblastomas. CDX-0125-TEI exhibited efficient antigen binding and internalization, and cytotoxicity at picomolar concentrations in cells with different expression of ALK on the cell surface. In vivo studies showed that CDX-0125-TEI is effective against ALK wild-type and mutant patient-derived xenograft models. These data demonstrate that ALK is a bona fide immunotherapeutic target and provide a rationale for clinical development of an ALK-ADC approach for neuroblastomas and other ALK-expressing childhood cancers such as rhabdomyosarcomas.