Anti-CD38 Therapy with Daratumumab for Relapsed/Refractory CD20-Negative Diffuse Large B-Cell Lymphoma
Language English Country Czech Republic Media print
Document type Journal Article
PubMed
32512655
DOI
10.14712/fb2020066010017
PII: file/5917/fb2020a0003.pdf
Knihovny.cz E-resources
- MeSH
- ADP-ribosyl Cyclase 1 antagonists & inhibitors MeSH
- Lymphoma, Large B-Cell, Diffuse * drug therapy MeSH
- Humans MeSH
- Membrane Glycoproteins antagonists & inhibitors MeSH
- Antibodies, Monoclonal therapeutic use MeSH
- Mice MeSH
- Tumor Microenvironment MeSH
- Antineoplastic Agents * therapeutic use MeSH
- Antineoplastic Combined Chemotherapy Protocols MeSH
- Rituximab therapeutic use MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- ADP-ribosyl Cyclase 1 MeSH
- CD38 protein, human MeSH Browser
- daratumumab MeSH Browser
- Membrane Glycoproteins MeSH
- Antibodies, Monoclonal MeSH
- Antineoplastic Agents * MeSH
- Rituximab MeSH
Diffuse large B-cell lymphoma (DLBCL) is the most common and one of the most aggressive subtypes of non-Hodgkin's lymphomas. Front-line therapy consists of chemotherapy in combination with anti-CD20 monoclonal antibody rituximab. Relapses after rituximab-based regimen have poor prognosis and call for new treatment options. Immunohistochemistry analysis of relapsed DLBCL often reveal CD20-negative lymphoma, which limits repeated use of rituximab in combination with salvage chemotherapy. CD38 is a surface antigen that binds to CD38, CD31/PECAM-1 and hyaluronic acid. CD38 is an important mediator of signal transmission from the microenvironment into the cell. Anti-CD38 monoclonal antibody daratumumab has been approved for the treatment of multiple myeloma. Expression of CD38 on the surface of DLBCL is highly variable (compared to strong expression on myeloma cells), but can be easily assessed by flow cytometry or immunohistochemistry. A patient-derived xenograft (PDX) model of CD20-negative, CD38-positive DLBCL derived from a patient with rituximab-refractory DLBCL was used for in vivo experiments. We demonstrated that daratumumab suppressed growth of subcutaneous PDX tumours significantly more effectively than rituximab. Analysis of tumours obtained from mice treated with daratumumab revealed down-regulation of surface CD38, suggesting endocytosis of CD38-daratumumab complexes. The results suggest a potential clinical use of daratumumab in combination with salvage chemotherapy in patients with relapses of CD20-negative DLBCL. In addition, daratumumab might potentially serve as a suitable antibody moiety for derivation of antibodydrug conjugates for the targeted delivery of toxic payloads to the lymphoma cells.
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