CD20 (188-196) – SLFLGILSV – Epitope of B cell CD20 receptor
CD20 (188-196) is a short part of a membrane phosphoprotein,CD20,which is expressed on the surface of B cells. CD20 receptor is an important target for immunotherapy against B cell lymphoma. CD20 epitopes are used in antibodies CD20 production,such as the production of the first monoclonal antibody to be approved for the treatment of lymphoma.
Applications of CD20 (188-196)
CD20 (188-196) is involved in research to generate cytotoxic T lymphocytes and stimulate CTL responses against B cell diseases. The production of specific T cells and IFN-γ are quantified by ELISPOT. CD20 (188-196) has been identified as a highly immunogenic HLA-A2 restricted peptide. Results suggest that CD20 (188-196) may serve in immunotherapeutic strategies especially for vaccine development against certain type of blood cancer.
CD20 (188-196) is also used in research on cell therapy as target for T cell receptor. In fact,T cells are modified in vivo to express specific T cell receptor and then inject modified cells in B cells cancer patient in order to recognized malignant B cells and treat them.
The purpose of these studies was to develop immunogenic peptides derived from the CD19 and CD20 self-antigens for the induction of antigen-specific CTLs against B-cell malignancies. A total of seven peptides were designed and examined for their HLA-A2.1 affinity and immunogenicity. Of these peptides,we identified two highly immunogenic HLA-A2.1-specific peptides,CD19150-158 (KLMSPKLYV) and CD20188-196 (SLFLGILSV),which were capable of inducing peptide-specific CTLs. The CTLs displayed HLA-A2.1-restricted and antigen-specific cytotoxicity against Burkitt’s lymphoma,chronic B cell leukemia,and multiple myeloma cell lines. The CD19 or CD20 peptide–specific CTL cytotoxicity was confirmed using HLA-A2.1+ T2 cells presenting the appropriate peptide. No cytotoxic activity was observed against T2 cells presenting the irrelevant MAGE-3 peptide or T2 cells alone. In addition,the CTLs displayed a significant (P < 0.05) increase in cell proliferation and IFN-γ secretion (>830 ng/mL) following restimulation with HLA-A2.1+/CD19+/CD20+ tumor cells. The CTLs also displayed a distinct phenotype consisting of a high percentage of CD69+/CD45RO+ and a low percentage of CD45RA+/CCR7+ CD4+ or CD8+ T cells characteristic of effector memory cell population. Cyclic guanosine 3′ ,5′-monophosphate culture conditions using serum-free AIM-V medium containing human AB serum,recombinant human interleukin 2 (Proleukin) and CD3/CD28 Dynabeads were developed resulting in a 35-fold expansion of CD20 peptide–specific CTLs. The expanded CD20-CTLs retained their cytotoxic activity (28-49%) against the Burkitt’s lymphoma cell line. In conclusion,we report here on the identification of novel immunogenic CD19150-158 (KLMSPKLYV) and CD20188-196 (SLFLGILSV) peptides that have immunotherapeutic potentials as peptide vaccines or targeted T-cell therapies for treating B-cell malignancies.
T cells engineered to express chimeric antigen receptors (CARs) targeted to CD19 are effective in treatment of B-lymphoid malignancies. However,CARs recognize all CD19 positive (pos) cells,and durable responses are linked to profound depletion of normal B cells. Here,we designed a strategy to specifically target patient B cells by utilizing the fact that T-cell receptors (TCRs),in contrast to CARs,are restricted by HLA. Two TCRs recognizing a peptide from CD20 (SLFLGILSV) in the context of foreign HLA-A*02:01 (CD20p/HLA-A2) were expressed as 2A-bicistronic constructs. T cells re-directed with the A23 and A94 TCR constructs efficiently recognized malignant HLA-A2(pos) B cells endogenously expressing CD20,including patient-derived follicular lymphoma and chronic lymphocytic leukemia (CLL) cells. In contrast,a wide range of HLA-A2(pos)CD20(neg) cells representing different tissue origins,and HLA-A2(neg)CD20(pos) cells,were not recognized. Cytotoxic T cells re-directed with CD20p/HLA-A2-specific TCRs or CD19 CARs responded with similar potencies to cells endogenously expressing comparable levels of CD20 and CD19. The CD20p/HLA-A2-specific TCRs recognized CD20p bound to HLA-A2 with high functional avidity. The results show that T cells expressing CD20p/HLA-A2-specific TCRs efficiently and specifically target B cells. When used in context of an HLA-haploidentical allogeneic stem cell transplantation where the donor is HLA-A2(neg) and the patient HLA-A2(pos),these T cells would selectively kill patient-derived B cells and allow reconstitution of the B-cell compartment with HLA-A2(neg) donor cells. These results should pave the way for clinical testing of T cells genetically engineered to target malignant B cells without permanent depletion of normal B cells.
3- Walseng E. et al. PLoS One. 10(4):e0119559 (2015)
Recently,technology has become available to generate soluble T-cell receptors (sTCRs) that contain the antigen recognition part. In contrast to antibodies,sTCRs recognize intracellular in addition to extracellular epitopes,potentially increasing the number of applications as reagents for target detection and immunotherapy. Moreover,recent data show that they can be used for identification of their natural peptide ligands in disease. Here we describe a new and simplified expression method for sTCRs in human cells and show that these sTCRs can be used for antigen-specific labeling and elimination of human target cells. Four different TCRs were solubilized by expression of constructs encoding the TCR alpha (α) and beta (β) chains lacking the transmembrane and intracellular domains,linked by a ribosomal skipping 2A sequence that facilitates equimolar production of the chains. Cell supernatants containing sTCRs labeled target cells directly in a peptide (p)-human leukocyte antigen (HLA)-specific manner. We demonstrated that a MART-1p/HLA-A*02:01-specific sTCR fused to a fluorescent protein,or multimerized onto magnetic nanoparticles,could be internalized. Moreover,we showed that this sTCR and two sTCRs recognizing CD20p/HLA-A*02:01 could mediate selective elimination of target cells expressing the relevant pHLA complex when tetramerized to streptavidin-conjugated toxin,demonstrating the potential for specific delivery of cargo. This simple and efficient method can be utilized to generate a wide range of minimally modified sTCRs from the naturally occurring TCR repertoire for antigen-specific detection and targeting.
Several novel anti-CD20 monoclonal antibodies are currently in development with the aim of improving the treatment of B cell malignancies. Mutagenesis and epitope mapping studies have revealed differences between the CD20 epitopes recognized by these antibodies. Recently,X-ray crystallography studies confirmed that the Type I CD20 antibody rituximab and the Type II CD20 antibody obinutuzumab (GA101) differ fundamentally in their interaction with CD20 despite recognizing a partially overlapping epitope on CD20. The Type I CD20 antibodies rituximab and ofatumumab are known to bind to different epitopes. The differences suggest that the biological properties of these antibodies are not solely determined by their core epitope sequences,but also depend on other factors,such as the elbow hinge angle,the orientation of the bound antibody and differential effects mediated by the Fc region of the antibody. Taken together,these factors may explain differences in the preclinical properties and clinical efficacy of anti-CD20 antibodies.
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