Monoclonal antibodies binding to different epitopes of CD20 differentially sensitize DLBCL to different classes of chemotherapy

Brian Lee; Tim Pierpont; Avery August; Kristy Richards

doi:10.3389/fonc.2023.1159484

Monoclonal antibodies binding to different epitopes of CD20 differentially sensitize DLBCL to different classes of chemotherapy

Front Oncol. 2023 Aug 3:13:1159484. doi: 10.3389/fonc.2023.1159484. eCollection 2023.

Authors

Brian Lee¹, Tim Pierpont², Avery August², Kristy Richards³

Affiliations

¹ Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, United States.
² Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States.
³ Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States.

Abstract

Introduction: Rituximab (R), an anti-CD20 monoclonal antibody (mAb) and the world's first approved antibody for oncology patients, was combined with the CHOP chemotherapy regimen and markedly improved the prognosis of all B- cell-derived lymphomas, the most common hematological malignancy worldwide. However, there is a 35% disease recurrence with no advancement in the first-line treatment since R was combined with the archetypal CHOP chemotherapy regimen nearly 30 years ago. There is evidence that R synergizes with chemotherapy, but the pharmacological interactions between R and CHOP or between newer anti-CD20 mAbs and CHOP remain largely unexplored.

Methods: We used in vitro models to score pharmacological interactions between R and CHOP across various lymphoma cell lines. We compared these pharmacological interactions to ofatumumab, a second-generation anti-CD20 mAb, and CHOP. Lastly, we used RNA-sequencing to characterize the transcriptional profiles induced by these two antibodies and potential molecular pathways that mediate their different effects.

Results: We discovered vast heterogeneity in the pharmacological interactions between R and CHOP in a way not predicted by the current clinical classification. We then discovered that R and ofatumumab differentially synergize with the cytotoxic and cytostatic capabilities of CHOP in separate distinct subsets of B-cell lymphoma cell lines, thereby expanding favorable immunochemotherapy interactions across a greater range of cell lines beyond those induced by R-CHOP. Lastly, we discovered these two mAbs differentially modulate genes enriched in the JNK and p38 MAPK family, which regulates apoptosis and proliferation.

Discussion: Our findings were completely unexpected because these mAbs were long considered to be biological and clinical equivalents but, in practice, may perform better than the other in a patient-specific manner. This finding may have immediate clinical significance because both immunochemotherapy combinations are already FDA-approved with no difference in toxicity across phase I, II, and III clinical trials. Therefore, this finding could inform a new precision medicine strategy to provide additional therapeutic benefit to patients with B-cell lymphoma using immunochemotherapy combinations that already meet the clinical standard of care.

Keywords: B-cell lymphoma; DLBCL; R-CHOP; chemotherapy; ofatumumab; rituximab.

Grants and funding

This work was supported, in part, by grants from the Dextra Undergraduate Research Endowment, Cornell Agriculture and Life Sciences Endowment, Paul Schreuers Memorial Endowment, Goldberg Foundation, National Institutes of Health (5R01 CA185372 to KR, TP, and BL and T32GM008152-35 to BL), and National Institute of Allergy and Infectious Diseases (AI29422, AI120701, and AI138570 to AA and TP).