On September 16, 2025 Researchers at Children’s Hospital of Philadelphia (CHOP) reported a novel antibody-drug conjugate (ADC) that shows striking efficacy against cancers that express the anaplastic lymphoma kinase (ALK) protein on the cancer cell surface (Press release, CHOP, SEP 16, 2025, View Source [SID1234656009]). The therapy, named CDX0239-PBD, achieved complete and lasting tumor responses in preclinical models of neuroblastoma, rhabdomyosarcoma and colorectal carcinoma, according to findings published in Nature Communications. The breakthrough could unlock a new class of precision medicine treatments for both childhood and adult cancers, potentially improving short- and long-term patient outcomes and minimizing the harmful side effects of many current treatments.
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Yael P. Mossé, MD, Professor of Pediatrics and leader of the Neuroblastoma Developmental Therapeutics Program at CHOP’s Cancer Center, and her team are renowned for the groundbreaking discovery of gain-of-function mutations in the ALK gene, which are the primary cause of hereditary neuroblastoma and the most common mutations in its sporadic forms. This discovery was pivotal as it identifies ALK as the only mutated oncogene in neuroblastoma that can be targeted for therapy, reducing the likelihood of toxic side effects. The new research, an outgrowth of Mossé’s work, was led by Alberto D. Guerra, MD, PhD, a fellow within the Division of Oncology at CHOP.
In the study, researchers combined CDX0239, a humanized antibody targeting ALK, with a potent chemotherapy agent called pyrrolobenzodiazepine (PBD) dimer. This innovative approach directs the antibody to cancer cells, delivering the chemotherapy inside to kill cancerous cells while mostly sparing healthy ones that do not express ALK. The ADC remained stable in the bloodstream, an essential step for moving the research into human trials.
"Our findings represent an important advance in the field of antibody-drug conjugates for pediatric solid tumors, an area where progress has lagged," said Guerra. "By combining tumor selectivity with potent drug delivery, CDX0239-PBD offers a potential blueprint for future pediatric solid tumor therapies."
The therapy’s effectiveness is closely linked to ALK levels on the surface of cancer cells. Those with a range of ALK surface expression responded well, even when expression was modest. This is particularly exciting as these findings credential the opportunity to leverage an ADC approach for a broad population of patients. In preclinical studies with human tumor models, three total weekly doses of CDX0239-PBD successfully eliminated tumors, resulting in 100% survival across several highly drug-resistant preclinical models. The effects were seen not only in pediatric cancers like neuroblastoma and rhabdomyosarcoma but also in colorectal carcinoma, underscoring the treatment’s potential versatility.
The therapy also achieved success where others did not. For example, in models resistant to lorlatinib, an FDA-approved ALK inhibitor, and those with TP53 mutations and MYCN amplification, treatment with CDX0239-PBD led to lasting positive effects and complete survival. Molecular analyses confirmed that the treatment caused DNA damage and activated cell-death pathways inside tumors, validating its mechanism of action to be selective delivery of a potent chemotherapy drug to cancer cells expressing ALK, and likely also to neighboring tumor cells which may not necessarily express ALK, a phenomenon referred to as the "bystander effect."
Moving forward, the research team is working on refining the technology to meet strict regulatory requirements for developing a first-in-class ALK-directed ADC, aiming for first-in-human/first-in-children early phase clinical trial testing within the next two years. The team is also exploring alternative antibodies with features that would allow for better penetration into the solid tumor microenvironment.
"Precision medicine is transforming our approach to cancer treatment by moving beyond one-size-fits-all therapies," said Mossé. "By tailoring treatments to the unique characteristics of each tumor, we can specifically target cancer cells, thereby increasing the potency and reducing harmful side effects on healthy cells. Our hope is to significantly boost survival rates for patients fighting aggressive cancers while also enhancing their quality-of-life post-treatment."
This work was supported in part by the National Cancer Institute grants (R01CA140198-11-1, R37CA282041 and K08CA230223), Patricia Brophy Endowed Chair in Neuroblastoma Research, DOD Award (W81XWH-12-1-0486), the National Institutes of Health grant (R013208130624), the National Institutes of Health grant (DP2HD108775), funding from Braden’s Hope Foundation, the Margaret Q Landenberger Foundation, NIH Grant (2T32CA009615) and the Howard Hughes Medical Institute (HHMI).