人源化抗 CD33 CAR-T 细胞与抗体药物偶联物用于急性髓系白血病靶向治疗

Acute myeloid leukemia (AML) is a malignant disorder originating from myeloid hematopoietic stem and progenitor cells. Despite the availability of current treatment options, a significant number of patients fail to achieve complete remission after initial chemotherapy. CD33, a transmembrane protein highly expressed on AML cells, serves as a promising therapeutic target. This study aimed to develop and evaluate chimeric antigen receptor T cells (CAR-T) and antibody-drug conjugates (ADC) based on humanized antibodies, specifically targeting CD33, to assess their potential efficacy against AML.

Monoclonal antibodies specific to human CD33 were generated by immunizing mice and then humanized. These humanized antibodies were then used to construct CAR-T cells and ADCs, and their cytotoxic properties were evaluated both in vitro and in vivo . In the in vivo experiments, mice bearing Molm13-Luciferase tumor cells were assigned to different treatment groups and were administered with saline, Gemtuzumab-MMAE, or Clone3HM-MMAE.

The in vitro experiments revealed that several antibody clones, including Clone2HM, Clone3HM, Clone5HM, Clone6HM, and Clone7HM, displayed strong cytotoxic effects against Molm13-Luciferase tumor cells when conjugated with MMAE, outperforming the positive control antibody Gemtuzumab-MMAE. In the in vivo studies, mice treated with Clone3HM-MMAE showed a significant reduction in tumor signals, which nearly disappeared in the latter stages of the experiment. This led to a substantially longer survival time compared to other groups. Additionally, the body weight of mice in all treatment groups remained stable throughout the treatment period, indicating a favorable safety profile.

The CAR-T cells and ADCs developed in this study, based on humanized antibodies, showed significant anti-tumor efficacy in the AML model. Clone3HM-MMAE, in particular, demonstrated excellent anti-tumor activity along with a strong safety profile. These results strongly support the further development of targeted therapeutic strategies for AML.