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.
The aim of our study was to evaluate antibodies against thyroglobulin (anti-TG) and thyroid peroxidase (anti-TPO) – markers of autoimmune thyroiditis – in several groups of adult patients with type 1 and type 2 diabetes mellitus (DM). We were particularly interested whether the presence of thyroid antibodies is related to the positivity of glutamic acid decarboxylase antibodies (anti-GAD). We found elevated anti-GAD in 46 % (97/210) patients with type 1 DM. All patients with type 2 diabetes were anti-GAD-negative. At least one thyroid antibody (anti-TG and/or anti-TPO) was found in 30 % (62/210) patients with type 1 DM and 27 % (22/83) type 2 diabetes patients. The patients with type 1 DM were further grouped according to their anti-GAD status. The anti-GAD-positive patients had a higher prevalence of anti-TG antibodies than the anti-GAD-negative patients (25 % vs. 12 %, p=0.03) as well as anti-TPO antibodies (32 % vs. 12 %, p<0.001). At least one thyroid antibody was detected in 39 % (38/97) of anti-GAD-positive but only in 21 % (24/113) of anti-GAD-negative patients with type 1 DM (p=0.006). No significant difference in the frequency of thyroid antibodies was found between anti-GAD-negative patients with type 1 and type 2 DM (21 % vs. 27 %, p=0.4). The groups with or without thyroid antibodies in both type 1 and type 2 diabetic patients did not differ in actual age, the age at diabetes onset, duration of diabetes, body mass index or HbA1c level. Patients with elevated thyroid antibodies had significantly higher levels of TSH than those without thyroid antibodies (1.86 vs. 3.22 mIU/l, p=0.04 in type 1 DM; 2.06 vs. 4.89 mIU/l, p=0.003 in type 2 DM). We conclude that there is a higher frequency of thyroid-specific antibodies in anti-GAD-positive adult patients with type 1 DM than in anti-GAD-negative patients or in patients with type 2 DM. Patients with or without thyroid antibodies do not differ in age, DM onset and duration, BMI or HbA1c. Thyroid antibodies-positive patients have higher levels of thyroid stimulating hormone (TSH).