Analysis of innate and acquired resistance to anti-CD20 antibodies in malignant and nonmalignant B cells

Abstract

The anti-CD20 monoclonal antibody, rituximab, provides a significant therapeutic benefit for patients with B-cell disorders. However, response to therapy varies and relapses are common, so an understanding of both inherited and acquired rituximab resistance is needed. In order to identify mechanisms of inherited resistance, sensitive versus resistant individuals were selected from a survey of 92 immortalized lymphoblastoid B-cell lines from normal individuals. Levels of CD20 protein and surface expression were lower in the resistant group. In contrast, CD20 mRNA levels were not correlated with susceptibility, suggesting regulation at a post-transcriptional level. To examine acquired resistance, resistant sublines were selected from both lymphoblastoid as well as lymphoma cell lines. Confirming previous findings, there was significant down-regulation of CD20 protein expression in all the resistant sublines. CD20 mRNA splice variants are reported to be associated with development of resistance. Three splice variants were observed in our cell lines, each lacking the binding epitope for rituximab, but none were associated with rituximab resistance. The second generation anti-CD20 mAb, ofatumumab, was more active compared with rituximab in vitro in the survey of all B-cell lines, mirroring results that have been reported previously with malignant B-cells. These studies show that normal B-lymphoblastoid cell lines can be used to model both innate and acquired mechanisms of resistance. They validate the important role of CD20 expression and enable future genetic studies to identify additional mediators of anti-CD20 mAb resistance.

Postulated Mechanisms of Resistance of B-Cell Non-Hodgkin Lymphoma to Rituximab Treatment Regimens: Strategies to Overcome Resistance

“…A survey 66 of 92 immortalized normal lymphoblastoid cell lines and separated for sensitive and resistant lines. The findings were as follows: (1) The level of CD20 protein and surface expression was decreased in the resistant lines.…”

Comparative Transcriptome Analysis of the Heat Stress Response in Monochamus alternatus Hope (Coleoptera: Cerambycidae)

“…De novo transcriptome assembly has been widely applied to detect and identify differential genes under different experimental conditions (He et al, 2017;Liu et al, , 2018Chen et al, 2018), enabling researchers to understand the molecular mechanism of action from a transcriptomics perspective. Different expression gene (DEGs) profiling in this technique presents the advantages of precision, economy, and repeatability, and has been widely used in plants to explore genes related to heat resistance (Li et al, 2015;Yan et al, 2016;Shi et al, 2017), while in insects, comparative transcriptome analysis related to heat responses has been only applied in several species, including G. pyloalis, Cryptolaemus montrouzieri, and Bombyx mori (Wang et al, 2014;Zhang Y.H.…”

Efficacy of an Anti-transferrin Receptor 1 Antibody Against AIDS-related Non-Hodgkin Lymphoma

“…Even though the overall incidence of AIDS-NHL has decreased during the cART era, HIV positive persons continue to be at risk and AIDS-NHL is the most common AIDS-related cancer in developed countries where poor survival rates remain problematic 11,12 . The clinical use of rituximab, an anti-CD20 IgG1, in combination with chemotherapy has improved the survival of many NHL patients; however, limited responses and the development of resistance to the treatment remain a challenge 13 . In this report we evaluated, for the first time, the anti-cancer activity of ch128.1 against an AIDS-NHL cell line both in vitro and in an animal model.…”