CD33-D2 isoform characterization for advancement of its therapeutic potential
Year: 2025
Type: article
Abstract: Purpose While CD33 directed immunotherapies have caught significant interest in recent years, the only approved antibody-drug conjugate targeting this antigen for AML is gemtuzumab ozogamicin, which targets the IgV-domain of CD33. Unfortunately, in its current form, these are not effective in a significant proportion of patients due to the presence of a splicing SNP resulting in the loss of IgV-domain. This, however, can be mitigated by targeting the IgC2-domain of CD33; thus, this study aimed to characterize CD33-D2 isoform using the recently developed CD33-D2-targeting antibody HL2541.Methods Genetically engineered AML cell lines expressing CD33 isoforms were tested for antibody-bound internalization and response to GO in vitro. AML-bearing NSG-SGM3 mice were used to evaluate CD33-D2 localization and targeting by the HL2541 antibody in vivo.Results HL2541-bound-CD33-D2 is internalized similar to CD33-FL upon binding the antibody component of GO. Co-existence of both isoforms compromises the internalization by >2.5–3-fold for each isoform in the AML cell lines, further resulting in 7–9.5-fold higher IC50 values compared to cells expressing only CD33-FL. Finally, we demonstrate that AML cells expressing CD33-D2 localize to bones in mice and are targeted by HL2541antibody in vivo.Conclusion The results establish the relevance of targeting IgC domain as an alternative immunotarget to supplement AML chemotherapy.
Source: Immunotherapy
Institutions: University of Florida, City Of Hope National Medical Center
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4409769243