An antibody-drug conjugate directed to the ALK receptor demonstrates efficacy in preclinical models of neuroblastoma
| Autor: | Yael P. Mosse, Colleen Larmour, Jay S. Lillquist, Bruce R. Pawel, Ulisse Cucchi, Kateryna Krytska, Diego Alvarado, Paolo Orsini, Pichai Raman, Daniel Martinez, Simona Rizzi, Gwenda F. Ligon, Renata Sano |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Alkylating Agents
Antibody-drug conjugate Immunoconjugates media_common.quotation_subject Cell Apoptosis Article Neuroblastoma In vivo hemic and lymphatic diseases medicine Animals Anaplastic Lymphoma Kinase Internalization Receptor Cytotoxicity media_common Cell Death biology business.industry Antibodies Monoclonal DNA General Medicine medicine.disease Xenograft Model Antitumor Assays Endocytosis Disease Models Animal Treatment Outcome medicine.anatomical_structure Cancer research biology.protein Antibody business DNA Damage |
| Zdroj: | Sci Transl Med |
| ISSN: | 1946-6242 1946-6234 |
| DOI: | 10.1126/scitranslmed.aau9732 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|