Cytokeratin 8-MHC class I interactions: a potential novel immune escape phenotype by a lymph node metastatic carcinoma cell line.

Defective human leukocyte antigen (HLA) class I expression in malignant cells facilitates their escape from destruction by CD8(+) cytotoxic T lymphocytes. In this study, a post-translational mechanism of HLA class I abnormality that does not involve defects in the HLA subunits and antigen processing machinery components was identified and characterized. The marked HLA class I downregulation phenotype of a metastatic carcinoma cell line can be readily reversed by trypsin, suggesting a masking effect by serine protease-sensitive HLA class I-interacting factors. Co-immunoprecipitation, combined with LC-tandem mass spectrometry and immunoblotting identified these factors as cytokeratin (CK) 8 and its heterodimeric partners CK18 and CK19. Ectopic CK8/18 or CK8/19 expression in HEK293 cells resulted in surface CK8 expression with an HLA class I downregulation phenotype, while redirecting CK8/18 and CK8/19 to the endoplasmic reticulum (ER) had no such effect. This observation and the failure to constrain CK8/18 and CK8/19 membrane trafficking by an ER-Golgi transport inhibitor suggested an ER-independent route for CK8 access to HLA class I molecules. Monoclonal antibody mapping revealed a potential CK8 blockade of HLA class I-CD8 and -TCR contacts. These findings, along with the emerging role of cell surface CK8 in cancer metastasis, may imply a dual strategy for tumor cell survival in the host.

IgE-neutralizing UB-221 mAb, distinct from omalizumab and ligelizumab, exhibits CD23-mediated IgE downregulation and relieves urticaria symptoms.

Over the last 2 decades, omalizumab is the only anti-IgE antibody that has been approved for asthma and chronic spontaneous urticaria (CSU). Ligelizumab, a higher-affinity anti-IgE mAb and the only rival viable candidate in late-stage clinical trials, showed anti-CSU efficacy superior to that of omalizumab in phase IIb but not in phase III. This report features the antigenic-functional characteristics of UB-221, an anti-IgE mAb of a newer class that is distinct from omalizumab and ligelizumab. UB-221, in free form, bound abundantly to CD23-occupied IgE and, in oligomeric mAb-IgE complex forms, freely engaged CD23, while ligelizumab reacted limitedly and omalizumab stayed inert toward CD23; these observations are consistent with UB-221 outperforming ligelizumab and omalizumab in CD23-mediated downregulation of IgE production. UB-221 bound IgE with a strong affinity to prevent FcԑRI-mediated basophil activation and degranulation, exhibiting superior IgE-neutralizing activity to that of omalizumab. UB-221 and ligelizumab bound cellular IgE and effectively neutralized IgE in sera of patients with atopic dermatitis with equal strength, while omalizumab lagged behind. A single UB-221 dose administered to cynomolgus macaques and human IgE (ε, κ)-knockin mice could induce rapid, pronounced serum-IgE reduction. A single UB-221 dose administered to patients with CSU in a first-in-human trial exhibited durable disease symptom relief in parallel with a rapid reduction in serum free-IgE level.