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Block-Removed Immunoglobulin Technology to enhance rituximab effector function by counteracting CA125-mediated immunosuppression.

ABSTRACT: Rituximab (RTX) is a CD20-targeting antibody that is the standard-of-care for patients with non-Hodgkin Lymphoma (NHL) cases. RTX's mechanism of action includes complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Recent clinical evidence suggests that high serum levels of the tumor-produced mucin 16 (MUC16) and cancer antigen 125 (CA125) have a negative impact on the effectiveness of RTX clinical activity in up to 40% of patients with follicular lymphoma. The present study sought to understand the possible mechanism underlying these results; therefore, cellular and molecular analyses of RTX and CA125 interaction were peformed, and a library of RTX variants was generated using a proprietary technology called Block-Removed Immunoglobulin Technology that combines randomized amino acid substitutions and high-throughput functional screenings to identify CA125-refractory RTX variants. The present study demonstrated that CA125 could bind to RTX and reduce its tumor cell killing activity. Furthermore, the study characterized an RTX variant, named NAV-006 (RTX-N109D), which was more refractory to the immunosuppressive effects mediated by CA125 as evidenced by its reduced CA125 interaction and increased activity of ADCC and CDC when compared with parent RTX. Taken together, these findings warranted further investigation on NAV-006 as a next generation anti-CD20 antibody that could improve the efficacy of parent RTX in NHL patients with high levels of CA125.

SUBMITTER: Grasso L

PROVIDER: S-EPMC8607236 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: We aimed to investigate the effects of intravenous immune globulin (IVIG) and rituximab desensitization treatment on kidney transplant rate and blood gene expression profiles by microrarrays. Methods: We enrolled patients with PRA levels >50% and on the deceased-donor waiting list for >5 years. Patients received IVIG (2.0 g/kg) on day 0 and 30; and rituximab (375 mg/m2) on day 15. The antibodies with mean fluorescence intensity (MFI) values > 5,000 were reported to UNET as unacceptable antigens. The gene expression profiles of blood samples collected in PAXGene tube were studied by Affymetrix HuGene 1.0 ST expression arrays. Results: 40 of the 415 patients (10%) on the waiting list were eligible for desensitization treatment and 11 completed the treatment. While 15 of the remaining 29 patients (52%) received a transplant without therapy, only 2 of the 11 desensitized patients (18%) received transplant during a median follow-up of 217 days. While there were no statistically significant difference in demographics, desensitized patients had higher cPRA values (97% vs. 77%, p=0.0005) and more number of unacceptable antigens (39 vs. 10, p=0.0001). There was no significant change in the mean number of unacceptable antigens (39 ± 22 versus 39 ± 23) or reduction in the mean MFI values (11,333 ± 3,133 vs 11,289 ± 3,386). Analysis of genes chosen as significantly differentially expressed revealed downregulation of genes involved in B cells and immune system (CD79a, B and T lymphocyte associated transcript, B cell scaffold protein, CD22, CXCR5, fas apoptotic inhibitory protein). Gene set enrichment analysis using Pathogenesis Based Transcripts created by Edmonton Group demonstrated significant downregulation of B cell associated (p=0.04) and immunoglobulin transcripts (p=0.03). Conclusion: Although, desensitization with IVIG and rituximab decreases the expression of B cell and immunoglobulin associated transcripts, it was not successful in increasing kidney transplant rate or in decreasing the number of unacceptable antigens.

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Block-Removed Immunoglobulin Technology to enhance rituximab effector function by counteracting CA125-mediated immunosuppression.

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