A humanized anaplastic lymphoma kinase (ALK)-directed antibody-drug conjugate with pyrrolobenzodiazepine payload demonstrates efficacy in ALK-expressing cancers

Alberto D. Guerra, Smita Matkar, Christina Acholla, Colleen Casey, Grant Li, Martina Mazzeschi, Khushbu Patel, Kateryna Krytska, Chuan Chen, Skye Balyasny, Joshua Kalna, Paul Kamitsuka, Mark Gerelus, Grace Polkosnik, David Groff, Apratim Mukherje, Cynthia Adams, Gabriela Witek, Amber K. Hamilton, Daniel Martinez, Jennifer Pogoriler, Timothy T. Spear, Yimei Li, Piotr Jung, Diego Alvarado, Mattia Lauriola, John M. Maris, Adam J. Wolpaw, Kristopher R. Bosse, Dimiter Dimitrov, Mustafa Mir, Dontcho V. Jelev and Yael P. Mossé ()
Additional contact information
Alberto D. Guerra: Division of Oncology and Center for Childhood Cancer Research
Smita Matkar: Division of Oncology and Center for Childhood Cancer Research
Christina Acholla: Division of Oncology and Center for Childhood Cancer Research
Colleen Casey: Division of Oncology and Center for Childhood Cancer Research
Grant Li: Division of Oncology and Center for Childhood Cancer Research
Martina Mazzeschi: IRCCS Azienda Ospedaliero-Universitaria di Bologna
Khushbu Patel: Division of Oncology and Center for Childhood Cancer Research
Kateryna Krytska: Division of Oncology and Center for Childhood Cancer Research
Chuan Chen: Center for Antibody Therapeutics
Skye Balyasny: Division of Oncology and Center for Childhood Cancer Research
Joshua Kalna: Division of Oncology and Center for Childhood Cancer Research
Paul Kamitsuka: Division of Oncology and Center for Childhood Cancer Research
Mark Gerelus: Division of Oncology and Center for Childhood Cancer Research
Grace Polkosnik: Division of Oncology and Center for Childhood Cancer Research
David Groff: Division of Oncology and Center for Childhood Cancer Research
Apratim Mukherje: Department of Cell and Developmental Biology
Cynthia Adams: Center for Antibody Therapeutics
Gabriela Witek: Division of Oncology and Center for Childhood Cancer Research
Amber K. Hamilton: Division of Oncology and Center for Childhood Cancer Research
Daniel Martinez: Division of Oncology and Center for Childhood Cancer Research
Jennifer Pogoriler: Division of Oncology and Center for Childhood Cancer Research
Timothy T. Spear: Division of Oncology and Center for Childhood Cancer Research
Yimei Li: Division of Oncology and Center for Childhood Cancer Research
Piotr Jung: Division of Oncology and Center for Childhood Cancer Research
Diego Alvarado: Antibody Therapeutics Department
Mattia Lauriola: IRCCS Azienda Ospedaliero-Universitaria di Bologna
John M. Maris: Division of Oncology and Center for Childhood Cancer Research
Adam J. Wolpaw: Division of Oncology and Center for Childhood Cancer Research
Kristopher R. Bosse: Division of Oncology and Center for Childhood Cancer Research
Dimiter Dimitrov: Center for Antibody Therapeutics
Mustafa Mir: Center for Computational and Genomic Medicine
Dontcho V. Jelev: Center for Antibody Therapeutics
Yael P. Mossé: Division of Oncology and Center for Childhood Cancer Research

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract The Anaplastic Lymphoma Kinase (ALK) gene is a receptor tyrosine kinase (RTK) with expression restricted to the developing nervous system. Most neuroblastomas express native ALK protein on the cell surface and ALK is uniformly overexpressed in fusion-positive rhabdomyosarcoma and in subsets of metastatic colorectal carcinoma, melanoma, ovarian carcinoma, and breast carcinoma. Here, we first confirm that ALK RNA, protein, and tumor cell surface expression is elevated in multiple pediatric and adult malignancies with minimal expression in childhood normal tissues. We then demonstrate that a humanized ALK-directed antibody conjugated to pyrrolobenzodiazepine (CDX0239-PBD) is internalized in ALK-expressing neuroblastoma cell lines with cell surface expression-dependent cytotoxicity. Finally, we show that CDX0239-PBD exhibits potent antitumor efficacy including maintained complete responses in ALK-expressing patient and cell line-derived neuroblastoma, fusion-positive rhabdomyosarcoma, and colorectal carcinoma xenograft models. These data support the clinical development of a first-in-class ALK-directed antibody-drug conjugate (ADC) for multiple pediatric and adult ALK-expressing malignancies.

Date: 2025
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DOI: 10.1038/s41467-025-62979-1

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