Glycoengineering of NK Cells with Glycan Ligands of CD22 and Selectins for B‐Cell Lymphoma Therapy

Abstract

CD22, a member of Siglec family of sialic acid binding proteins, has restricted expression on B cells. Antibody‐based agents targeting CD22 or CD20 on B lymphoma and leukemia cells exhibit clinical efficacy for treating these malignancies, but also attack normal B cells leading to immune deficiency. Here, we report a chemoenzymatic glycocalyx editing strategy to introduce high‐affinity and specific CD22 ligands onto NK‐92MI and cytokine‐induced natural killer cells to achieve tumor‐specific CD22 targeting. These CD22‐ligand modified cells exhibited significantly enhanced tumor cell binding and killing in vitro without harming healthy B cells. For effective lymphoma cell killing in vivo, we further functionalized CD22 ligand‐modified NK‐92MI cells with the E‐selectin ligand sialyl Lewis X to promote trafficking to bone marrow. The dual‐functionalized cells resulted in the efficient suppression of B lymphoma in a xenograft model. Our results suggest that natural killer cells modified with glycan ligands to CD22 and selectins promote both targeted killing of B lymphoma cells and improved trafficking to sites where the cancer cells reside, respectively.

Single-cell RNA sequencing reveals cell heterogeneity and transcriptome profile of breast cancer lymph node metastasis

“…Based on this finding, the CD52 antibody alemtuzumab can be a potential therapy specifically targeting metastatic breast cancer cells to further decelerate and even eliminate lymph node metastasis through re-activating T-cell immunity. PTPRC has been identified to bind to the inhibitory receptor CD22 and negatively regulate B-cell immunity [44,45]. This interaction initiated by PTPRC in breast cancer cells serves as another potential mechanism for immune escape during lymph node metastasis.…”

Activity-based directed evolution of a membrane editor in mammalian cells

“…Beyond the utility of superPLDs, this study is significant for expanding the scope of directed enzyme evolution in mammalian cells to include activity-based fluorescent labeling for enzyme engineering. Metabolic and chemoenzymatic labeling are popular strategies to probe or perturb various cellular events, including lipid metabolism 7,47 , glycosylation [48][49][50][51] , and other posttranslational modifications [52][53][54] . We envision that extension of our mammalian cell-based directed evolution platform to other enzyme classes will enable engineering of highly efficient enzymes capable of serving as editors of a wider set of biomolecules in mammalian cells.…”

Overcoming tumor resistance mechanisms in CAR-NK cell therapy

“…Apart from strategies modulating the expression of chemokine receptors, BM homing can be enhanced by promoting the interaction of NK cells with adhesion molecules like E-selectin. For instance, the treatment of NK-92MI cells with human fucosyltransferase 6 (FUT6) and GDP-fucose creates cell-surface E-selectin ligand sialyl Lewis X (sLeX) to improve migration to BM and increase the killing of Blymphoma cells (336). Besides, while augmenting NK cell expansion in culture, nicotinamide (NAM) leads to CD62L (L-selectin) upregulation (337) resulting in improved in vivo migration of adoptively transferred NK cells to multiple organs including the BM (338,339).…”