Innovative Preclinical Therapy Targets ALK Protein to Precisely Kill Tumors While Protecting Healthy Cells

Researchers at Children's Hospital of Philadelphia (CHOP) have developed a promising new antibody-drug conjugate (ADC) that shows significant effectiveness against cancers expressing the ALK (anaplastic lymphoma kinase) protein on their surface. Named CDX0239-PBD, this therapy achieved complete and durable tumor regression in preclinical models of neuroblastoma, rhabdomyosarcoma, and colorectal carcinoma. Published findings in Nature Communications reveal that this targeted approach may revolutionize treatment options for various cancers.

This breakthrough could pave the way for a new class of precision medicine therapies that not only improve clinical outcomes but also minimize the side effects associated with conventional treatments. The therapy hinges on an antibody (CDX0239) designed to specifically bind to ALK proteins on cancer cells, coupled with a potent chemotherapy agent, pyrrolobenzodiazepine (PBD) dimer. Once targeted, the ADC delivers the chemotherapy directly into cancer cells, sparing most healthy tissue, and remains stable in circulation—an important factor for advancing toward human trials.

Dr. Yael P. Mossé, a pediatric oncologist and leader of the Neuroblastoma Developmental Therapeutics Program at CHOP, emphasizes that ALK mutations are the key drivers in hereditary and some sporadic neuroblastomas. Because ALK is the only mutated oncogene in neuroblastoma that can be therapeutically targeted, this new approach offers a highly selective treatment option that could reduce toxicity.

The research conducted by Alberto D. Guerra, MD, Ph.D., and colleagues combined the ALK-specific antibody with PBD, a powerful cytotoxic compound. This combination directs the toxin specifically to tumor cells expressing ALK, inducing DNA damage and activating tumor cell death pathways. Importantly, the ADC demonstrated stability and effectiveness in preclinical models, including cases resistant to existing ALK inhibitors like lorlatinib, as well as tumors with genetic features such as TP53 mutations or MYCN amplification.

Multiple doses of CDX0239-PBD successfully eradicated tumors and resulted in 100% survival rates across diverse drug-resistant models. The therapy also exhibited a notable ‘bystander effect,’ damaging neighboring tumor cells that did not express ALK, further enhancing its efficacy.

Looking ahead, the team is working on optimizations necessary for regulatory approval and clinical testing. Efforts are underway to develop antibodies with improved tumor penetration and to plan for initial human and pediatric trials within the next two years. Dr. Mossé highlights that this approach exemplifies how precision medicine moves beyond one-size-fits-all strategies, aiming for targeted therapies that increase potency while reducing adverse effects—ultimately hopeful to improve survival and quality of life for patients with aggressive cancers.

For more details, see the original study by Guerra et al., published in Nature Communications, DOI: 10.1038/s41467-025-62979-1.