Anti-CD19 antibodies inhibit the function of the P-gp pump in multidrug-resistant B lymphoma cells
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Updated: Oct 18, 2026
Quantifying Antibody-Dependent Cellular Cytotoxicity in a Tumor Spheroid Model: Application for Drug Discovery
Published on: April 26, 2024
M A Ghetie1, V Ghetie, E S Vitetta
1The Cancer Immunobiology Center, University of Texas Southwestern Medical Center at Dallas, 75235-8576, USA.
Abstract:
After chemotherapy, tumor cells with multidrug resistance (MDR) often emerge. MDR is attributable to the expression of membrane transport proteins that inhibit the cellular influx and increase the efflux of many chemotherapeutic drugs. One such protein is P-glycoprotein (P-gp), which functions as an ATP-dependent active transporter. Recently, an anti-P-gp monoclonal antibody (MAb) that inhibits P-gp has been described. Previous studies from our laboratory using the anti-CD19 B-cell lymphoma-reactive MAb, HD37, have suggested that HD37 may also influence MDR. To test this directly, we used Namalwa/MDR1 cells to study the effect of HD37 on the efflux of rhodamine 123 from these cells. We found that HD37 and three other anti-CD19 MAbs inhibited the efflux of rhodamine 123 from Namalwa/MDR1 cells with approximately 50% of the efficiency of the well-known chemosensitizer, verapamil. In contrast, MAbs against seven other molecules expressed on these cells were ineffective. The inhibitory activity of HD37 did not require an Fc portion; F(ab')2 fragments were effective, but Fab' fragments were not, suggesting that higher avidity binding and/or cross-linking of CD19 are necessary. We could find no evidence that HD37 recognizes a cross-reactive epitope on P-gp, modulates P-gp from the cell surface, or enhances the ATPase activity of membranes from treated cells.
Insights
Anti-CD19 monoclonal antibodies (MAbs), including HD37, can inhibit multidrug resistance (MDR) in cancer cells by reducing drug efflux. This suggests a potential new strategy for overcoming chemotherapy resistance.
Area of Science:
- Cancer Biology
- Immunology
- Pharmacology
Background:
- Multidrug resistance (MDR) in tumor cells, often emerging after chemotherapy, is a significant clinical challenge.
- MDR is frequently mediated by membrane transport proteins like P-glycoprotein (P-gp) that actively efflux chemotherapeutic drugs.
- Previous research suggested a potential role for the anti-CD19 monoclonal antibody (MAb) HD37 in influencing MDR.
Purpose of the Study:
- To directly investigate the effect of the anti-CD19 MAb HD37 on multidrug resistance (MDR) in cancer cells.
- To determine if HD37 can inhibit the efflux of chemotherapeutic drugs mediated by P-glycoprotein (P-gp).
Main Methods:
- Utilized Namalwa/MDR1 cells, a model for multidrug resistance.
- Assessed the effect of HD37 and other anti-CD19 MAbs on the efflux of rhodamine 123, a substrate for P-gp.
- Compared the efficacy of HD37 with the known chemosensitizer verapamil and tested antibody fragments (F(ab')2, Fab') to understand binding requirements.
Main Results:
- HD37 and three other anti-CD19 MAbs significantly inhibited rhodamine 123 efflux from Namalwa/MDR1 cells.
- The inhibitory efficiency was approximately 50% of that observed with verapamil.
- MAbs targeting other cell surface molecules did not affect drug efflux, and inhibitory activity required higher avidity binding or cross-linking of CD19, not Fc-mediated effects.
Conclusions:
- Anti-CD19 MAbs, including HD37, can effectively reduce the efflux of drugs mediated by P-gp in MDR cancer cells.
- The mechanism does not involve direct interaction with P-gp but likely relies on CD19 binding characteristics.
- These findings highlight anti-CD19 MAbs as potential agents to overcome chemotherapy resistance in B-cell malignancies.
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