GT-008:一种可实现对CD24肿瘤相关糖基化形式选择性放射性核素递送的单克隆抗体——临床前概念验证研究

Aberrant O-glycosylation is a hallmark of cancer and many tumor-associated proteins carry truncated O-glycans like Tn or TF antigens. CD24 is a glycoprotein with a fundamental role in tumorigenesis, expressed on solid tumors, but also on selected normal cell types. We developed a humanized IgG1 mAb (GT-008) which binds CD24 only in presence of tumor-associated TF (core-1) glycosylation with limited abundance on normal tissues. This glycoform-selective recognition enables GT-008 to distinguish tumor from normal CD24 and mediate its mode of action in a tumor-selective manner. Unlike protein-specific anti-CD24 antibodies that block the “don't-eat-me” checkpoint, GT-008 exploits its glycosylation-dependent binding of CD24 for direct cytotoxic activity, including selective radionuclide delivery to tumors. Binding specificity and tumor selectivity of GT-008 was analyzed by ELISA, FACS and immunohistochemistry. After bioconjugation and radiolabeling, in vitro validation comprised binding and internalization assays with breast cancer cell lines. The pharmacokinetic profile of GT-008 was analyzed in athymic nude mice. Biodistribution and efficacy studies were performed in a cell-line derived xenograft breast cancer model. GT-008 demonstrated selective recognition of cancerous tissues, including including female cancers of the breast, endometrium and ovaries. It exhibited high-affinity binding in the low nM range and internalization in breast cancer cells, while showing no internalization in healthy CD24+ immune cells. Biodistribution studies showed specific and stable uptake in MCF7 tumors and clearance from other organs resulting in high tumor-to-organ ratios. Therapeutic single doses of GT-008 labeled with alpha or beta radiation emitting isotopes ( 225 Ac-GT-008, 10 + 3 kBq; 177 Lu-GT-008, 10 + 3 MBq) resulted in robust control of MCF7 breast tumors. Due to the high linear energy transfer and potent DNA-damaging capacity of alpha-emitters, ²²⁵Ac-GT-008 achieved superior tumor growth inhibition and a higher rate of complete remissions compared with ¹⁷⁷Lu-GT-008. All treatments were well tolerated. These findings supports the development of GT-008 as a theranostic radioligand for solid tumors, including female cancers, while supporting its broader potential across CD24-directed modalities such as ADCs, bispecifics, and cellular CAR therapies.