The glycosaminoglycan oncofetal chondroitin sulfate is a novel target for antibody-drug conjugate therapy for AML.

Antibody-drug conjugates (ADCs) have emerged as promising targeted therapies for acute myeloid leukemia (AML). However, most ADCs exhibit off-target binding to normal hematopoietic stem and myeloid progenitor cells, resulting in adverse hematotoxicity and narrow therapeutic windows, thereby limiting their clinical application to young and fit patients with AML who are eligible for intensive curative therapies. Proteoglycans with high levels of the glycosaminoglycan oncofetal chondroitin sulfate (ofCS) are abundantly expressed in solid cancers but are absent or expressed at low levels in normal adult tissues. Here, we report high ofCS levels on bone marrow (BM) cells from patients with AML and patient-derived xenografts (PDXs) from these patients, whereas BM cells from healthy individuals showed low or undetectable ofCS levels. Consistently, an anti-ofCS antibody demonstrated binding to and internalization into AML cells, and anti-ofCS ADCs effectively killed AML cells in vitro. Moreover, anti-ofCS ADC treatment significantly prolonged survival of AML PDXs compared with controls and was associated with low toxicity. Thus, anti-ofCS ADCs could represent an effective therapy with acceptable toxicity for patients with AML, including those who are ineligible for or unresponsive to current intensive curative therapies. In conclusion, this study demonstrates, to our knowledge for the first time, that a glycosaminoglycan-like ofCS is a druggable target for the development of effective antibody-based AML therapies.