A humanized anaplastic lymphoma kinase (ALK)-directed antibody-drug conjugate with pyrrolobenzodiazepine payload demonstrates efficacy in ALK-expressing cancers
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.
Article Details
Authors (33)
Alberto D. Guerra
Smita Matkar
Christina Acholla
Colleen Casey
Grant Li
Martina Mazzeschi
Khushbu Patel
Kateryna Krytska
Chuan Chen
Beijing Genomics Institute Research
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
Yael P. Mossé