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CD3-CD20-positive nodal lymphoma with cross-lineage rearrangement in a dog.

ABSTRACT: A 7-y-old mixed-breed male dog was presented with a history of generalized lymphadenopathy. Fine-needle aspirates of the enlarged peripheral lymph nodes were suggestive of lymphoma. Histologic examination of a retromandibular lymph node was suggestive of high-grade, medium large-cell lymphoma. Immunohistochemistry revealed concurrent expression of CD3 and CD20. The co-localization of the 2 antigens was confirmed by immunofluorescence. PCR for antigen receptor gene rearrangements (PARR) detected clonal rearrangements for both T-cell receptor gamma and B-cell receptor. The final diagnosis was CD3-CD20-positive anaplastic lymphoma with cross-lineage rearrangement.

SUBMITTER: Nicoletti A

PROVIDER: S-EPMC7649537 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:B-cell lymphoma is a group of malignant proliferative diseases originating from lymphoid tissue with different clinical manifestations and biological characteristics. It can occur in any part of the body, accounting for more than 80% of all lymphomas. The present study aimed to construct bispecific single-domain antibodies against CD20 and CD3 and to evaluate their function in killing tumor cells in vitro. A Bactrian camel was immunized with a human CD20 extracellular peptide, and the VHH gene was cloned and ligated into a phagemid vector to construct the phage antibody display library. A phage antibody library with a size of 1.2 × 108 was successfully constructed, and the VHH gene insertion rate was 91.7%. Ninety-two individual clones were randomly picked and screened by phage ELISA. Six strains with the high binding ability to human CD20 were named 11, 30, 71, 72, 83, and 92, and induced expression and purification were performed to obtain soluble CD20 single-domain antibodies. The obtained single-domain antibodies could specifically bind to human CD20 polypeptide and cell surface-expressed CD20 molecules in ELISA, Western blot, and cell immunofluorescence assays. The anti-CD20/CD3 bispecific nanobody (BsNb) was successfully constructed by fusing the anti-CD20 VHH gene with the anti-CD3 VHH and the bispecific single-domain antibody was expressed, purified, and validated. Anti-CD20/CD3 BsNb can specifically bind CD20 molecules on the surface of human lymphoma Raji cells and CD3 molecules on the surface of T cells in flow cytometry analysis and effectively mediate peripheral blood mononuclear cells (PBMCs) target Raji cells with a killing efficiency of up to 30.4%, as measured by the lactate dehydrogenase (LDH) method. The release of hIFN-γ from PBMCs during incubation with anti-CD20/CD3 BsNb was significantly higher than that of the control group (p < 0.01). The anti-CD20/CD3 BsNb could maintain 80% binding activity after incubation with human serum at 37 °C for 48 h. These results indicated the strong antitumor effect of the constructed anti-CD20/CD3 BsNb and laid the foundation for the further development of antitumor agents and the clinical application of anti-CD20/CD3 BsNb.

Project description:OBJECTIVE:This study was designed to determine the safety, pharmacokinetics and biologic effects of a human-mouse chimeric anti-CD20 monoclonal antibody (SCT400) in Chinese patients with CD20-positive B-cell non-Hodgkin's lymphoma (CD20(+) B-cell NHL). SCT400 has an identical amino acid sequence as rituximab, with the exception of one amino acid in the CH1 domain of the heavy chain, which is common in Asians. METHODS:Fifteen patients with CD20(+) B-cell NHL received dose-escalating SCT400 infusions (250 mg/m(2): n=3; 375 mg/m(2): n=9; 500 mg/m(2): n=3) once weekly for 4 consecutive weeks with a 24-week follow-up period. The data of all patients were collected for pharmacokinetics and pharmacodynamics analyses. RESULTS:No dose-limiting toxicities were observed. Most drug-related adverse events were grade 1 or 2. Two patients had grade 3 or 4 neutropenia. Under premedication, the drug-related infusion reaction was mild. A rapid, profound and durable depletion of circulating B cells was observed in all dose groups without significant effects on T cell count, natural killer (NK) cell count or immunoglobulin levels. No patient developed anti-SCT400 antibodies during the course of the study. SCT400 serum half-life (T1/2), maximum concentration (Cmax) and area under the curve (AUC) generally increased between the first and fourth infusions (P<0.05). At the 375 mg/m(2) dose, the T1/2 was 122.5±46.7 h vs. 197.0±75.0 h, respectively, and the Cmax was 200.6±20.2 g/mL vs. 339.1±71.0 g/mL, respectively. From 250 mg/m(2) to 500 mg/m(2), the Cmax and AUC increased significantly in a dose-dependent manner (P<0.05). Patients with a high tumor burden had markedly lower serum SCT400 concentrations compared with those without or with a low tumor burden. Of the 9 assessable patients, 1 achieved complete response and 2 achieved partial responses. CONCLUSIONS:SCT400 is well-tolerated and has encouraging preliminary efficacy in Chinese patients with CD20(+) B-cell NHL.

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CD3-CD20-positive nodal lymphoma with cross-lineage rearrangement in a dog.

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