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Immunomodulatory Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Another problem for all the CD19-targeted CAR-T therapies is down-regulation of the antigen via two distinct mechanisms: antigen escape or lineage switch. Antigen escape is where the patient relapses with a phenotypically comparable disease which lacks surface expression of CD19 and so is resistant to anti-CD19 CAR-T cell attack. Lineage switch is where a patient relapses with a genetically related but phenotypically distinct disease, most often AML. To prevent epitope spreading and to counter immune escape, the use of a combination of CAR-T cells with other therapies has been suggested. For example, Kite Pharma is currently evaluating the use of YescartaTM in combination with utomilumab (an anti-4-1BB monoclonal antibody) or atezolimumab (an anti-PDL1 antibody) in adults with refractory large B-cell lymphoma with improvements in ORR and CR observed.
Overview of the mucosal immune system structure
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Reinhard Pabst, Per Brandtzaeg
The complement receptors CR1/CR2 (CD35/CD21) are crucial in the germinal center reaction. CD21 is expressed abundantly on both B cells and FDCs and may thus function not only by localizing antigen to the FDCs but also by lowering the threshold of B-cell activation via recruitment of CD19 into the BCR. Activation of complement on FDCs bearing immune complexes is controlled by regulatory factors, but some release of inflammatory mediators may induce edema that facilitates dispersion of FDC-derived “immune complex-coated bodies,” or iccosomes, thereby enhancing the BCR-mediated uptake of their contained antigens by the B cells.
B Cells and Humoral Immunity
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
CD 19 and CD21 occur on the B cell membrane in a complex with CD81 (ΤΑΡΑ-1) and Leu 13. This complex may also associate with class II histocompatibility molecules. This complex has an important role in B cell activation (see below). CD21 (also called CR2) is the receptor for the C3d complement fragment and Epstein-Barr virus (EBV). CD21 is found on the majority of lymphoid organ B cells, but is infrequent among peripheral blood B cells. Aggregated C3d provides a growth signal for B cells; CD21 is not expressed after B cell activation.
B cell depletion and inhibition in systemic lupus erythematosus
Published in Expert Review of Clinical Immunology, 2023
Eugene Krustev, Ann E. Clarke, Megan R.W. Barber
Obexelimab (XmAb5871) is a humanized anti-CD19 mAb. CD19 is a surface molecule that is present on all B cells [9]. Obexelimab was bioengineered for increased affinity to FcγRIIb, an inhibitory receptor expressed on B cells and plasma cells, as well as several other effector cell types [9]. In a phase II placebo controlled RCT, 104 SLE patients with moderate disease activity underwent a screening phase where they were treated with Depo-Medrol. Patients who showed improvement with steroid therapy were then randomized to receive either obexelimab (5 mg/kg IV) or placebo, in addition to antimalarials and prednisone (maximum 10 mg per day) [57]. Loss of improvement was the primary endpoint and was not significant between groups in an efficacy evaluable population analysis. There was a significant difference in the intent to treat analysis at 169 days, but not at 225 days. Due to these mixed results, further development of obexelimab as an SLE therapy has been stopped.
TNB-486 induces potent tumor cell cytotoxicity coupled with low cytokine release in preclinical models of B-NHL
Published in mAbs, 2021
Harbani K. Malik-Chaudhry, Kirthana Prabhakar, Harshad S. Ugamraj, Andrew A. Boudreau, Benjamin Buelow, Kevin Dang, Laura M. Davison, Katherine E. Harris, Brett Jorgensen, Heather Ogana, Duy Pham, Ute Schellenberger, Wim Van Schooten, Roland Buelow, Suhasini Iyer, Nathan D. Trinklein, Udaya S. Rangaswamy
Based on the success of Rituxan®, lineage markers gained popularity as targets for the treatment of hematologic malignancies. CD19 is a B cell restricted surface receptor present on all B cells, including neoplastic B cells. The expression of CD19 is broader than CD20, from the pro-B cell to plasmablast stage, and is lost upon differentiation into plasma cells, making it a popular target for B cell malignancies.4,5 Efforts to target CD19 have included multiple immunotherapy modalities such as mAbs and their derivatives, e.g., antibody-drug conjugates (ADCs), T cell engaging bispecific antibodies (T-BsAbs), and chimeric antigen receptor (CAR)-T cells.5–7 Of these, mAbs have shown limited success, likely owing to lower antigen density of CD19 on malignant B cells compared to CD20,8 the inherently limited antibody-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity activities of mAbs, or rapid internalization of CD19 upon antibody crosslinking.5 CD19-targeted ADCs have also faced hurdles due to toxicity associated with the cytotoxic payload or inhibition of internalization due to high CD21 expression.9,10
Treatment and outcome of Philadelphia chromosome-positive acute lymphoblastic leukemia in adults after relapse
Published in Expert Review of Anticancer Therapy, 2020
Marie Balsat, Victoria Cacheux, Martin Carre, Emmanuelle Tavernier-Tardy, Xavier Thomas
CD19 is a 95-kDa transmembrane protein that appears early during B-cell development and persists throughout B-cell differentiation. Its activation results in the phosphorylation of tyrosine residues that mediate downstream signaling pathways involved in B-cell function [83] and in an effect on B-cell development, differentiation, and function in a B-cell receptor complex-independent manner [83,84]. Because CD19 is present on nearly all B-cell progenitor ALL cells, it represents an attractive target for the treatment of this type of ALL, which includes Ph-positive ALL. Blinatumomab is a CD19/CD3 bispecific BiTE antibody of 55-kDa. This fusion protein, which is made of two single-chain antibodies that have CD19 and CD3 specificities, respectively, connected by a short non-immunogenic linker, has been designed to redirect previously unstimulated T cells toward leukemic B cells to induce their lysis [85] (Figure 1). Lysis of malignant cells is primarily mediated by the perforin and granzyme from the cytotoxic T cells. Following blinatumomab administration, activation of polyclonal T cells results in a transient release of cytokines occurring mainly during the first cycle of treatment. T cells decline within one day of treatment but re-expand from the effector memory T-cell compartment within a few days to reach higher levels after 2–3 weeks. B cells counts drop within two days of treatment and remain low throughout therapy [86].