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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In preclinical models, both inotuzumab ozogamicin and the equivalent unconjugated human antibody (G5/44) were shown to bind CD22 with sub-nanomolar affinity, although only inotuzumab ozogamicin had potent picomolar cytotoxicity in CD22+ve B-cell lymphoma cell lines. Similarly, in in vivo efficacy studies, the single anti-CD22 monoclonal antibody was inactive whereas the ADC was efficacious.
Monocyte and lymphocyte membrane markers: Ontogeny and clinical significance
Published in Gabriel Virella, Medical Immunology, 2019
Scott Sugden, Damien Montamat-Sicotte, Karen K. Yam, Joseph Murphy, Bader Yassine Diab, Virginia Litwin
CD22, an integral part of the B-cell receptor complex, is first detected in the cytoplasm of pre-B-II cells containing cytoplasmic μ chains. Later, it is found on the surface of 75% of sIgM+ immature B cells, and on 90% of sIgM+, sIgD+ mature, resting cells. In the adult, CD22 is expressed at relatively high levels in tissue B cells (e.g., in the tonsils and lymph nodes) but not in circulating B cells. CD22 is upregulated during activation but is lost in the terminally differentiated plasma cells. CD22 binds to sialylated carbohydrate ligands (e.g., CD45RO) and plays an important regulatory role in B-cell activation by raising the B-cell activation threshold. CD22-deficient mice produce excessive antibody responses to antigen stimulation, as well as increased levels of autoantibodies. In contrast, cross-linking of CD22 suppresses the response of B cells to antigenic stimulation because the intracytoplasmic segment has numerous ITIM motifs that function as docking sites for SHP-1. The binding of SHP-1 to CD22 prevents phosphorylation of the kinases needed for further B-cell activation. In this way, CD19 and CD22 cross-regulate each other because activation through CD22 inhibits the CD19 pathway.
Radioimmunotherapy of Hematological Malignancies
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
From these initial investigations, the CD20 antigen emerged as having many of the characteristics thought to be important for a good tumor target and therefore targeting this antigen has dominated clinical RIT of lymphoma (10). The CD20 antigen is a transmembrane phosphoprotein that is expressed on mature B lymphocytes and to a lower degree on pre-B lymphocytes at a higher density. The antigen is also expressed on greater than 90% of B-cell NHL. The CD20 complex does not internalize or shed from the cell surface and initiates signal transduction that triggers apoptosis through a caspase-dependent pathway (11). CD20 is highly expressed on the majority of B-cell lymphomas but is not expressed on stem cells or plasma cells and consequently following radiolabeled anti-CD20 mAb RIT, the B-cell pool is replenished over the next few months. Although most clinical RIT work has been targeted against the CD20 antigen, other B-cell antigens such as CD22 are still being actively investigated (12).
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
Targeting B cell-expressed surface molecules using highly selective monoclonal antibodies (mAbs) can induce B cell depletion and is a well-studied therapeutic target in SLE. CD20 is a surface protein that is widely expressed on B cells during multiple stages of development; however, it is not expressed on pro-B cells and plasma cells. Although not fully understood, CD20 likely functions as a calcium channel [11,12]. Rituximab, obinutuzumab, ocrelizumab, and ofatumumab are all anti-CD20 mAbs that have been tested in SLE. CD22 is another cell surface molecule that is primarily expressed on B cells, but not on plasma cells or pro-B cells [13]. CD22 functions as a regulatory molecule and inhibits B cell overactivation [14]. A single anti-CD22 mAb, epratuzumab, has been tested in SLE. Lastly, obexelimab, a CD19-targeted agent, has also been tested in SLE.
Approaches for refining and furthering the development of CAR-based T cell therapies for solid malignancies
Published in Expert Opinion on Drug Discovery, 2021
The potential for targeting two distinct antigens has been demonstrated in B-cell malignancies and multiple myeloma. CAR T cells targeting the B-cell maturation antigen (BCMA) produced rapid tumor responses; however, durable remissions required high doses and upon relapse loss of BCMA expression was reported [26]. To overcome this, a second antigen, transmembrane activator and calcium-modulator and cyclophilin ligand (TACI), was targeted alongside BCMA and prevented tumor escape when compared to targeting BCMA alone [27]. A similar story has been presented in glioblastoma using a single tandem (Tan)CAR to target both HER2 and IL13Rα2. To achieve dual specificity, the targeting domain of the CAR consisted of a high-affinity IL13 mutein linked to a HER2-specific scFV. In mouse models, tanCARs mitigated antigen escape and led to improved survival [28]. Dual targeting of CD19 and CD22 with two 2nd generation CARs has been trialed in patients with diffuse large B-cell lymphoma producing complete responses in 55% of patients dosed with at least 50 × 106 CAR T cells [29].
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
CD22 is a 135-kDa sialoglycoprotein that mediates intercellular interactions for sialic-acid bearing ligands and modulates antigen receptor signaling and B-cell activation. CD22 is an important B cell-restricted surface antigen that is expressed in 96% of B cell-lineage ALL [103]. It is rapidly internalized on binding to anti-CD22 making it an attractive target for targeted therapy with chemotherapeutic conjugates. Following the development of gemtuzumab ozogamicin, an anti-CD33 antibody-drug conjugate, in acute myeloid leukemia, inotuzumab ozogamicin, an anti-CD22 antibody-drug conjugate, was developed. Inotuzumab ozogamicin is a humanized MoAb against CD22 conjugated via a bi-functional linker to a potent cytotoxic agent calicheamicin derived from Micromonospora echinospora, which induces DNA double-strand breaks and apoptosis independent of cell cycle progression [104]. Upon binding to CD22 receptors, inotuzumab is rapidly internalized, trafficked through lysosomes leading to hydrolysis of inactive calicheamicin. Calicheamicin is then reduced to its active form by intracellular glutathione. In the nucleus, active calicheamicin binds to DNA and generates free radicals leading to DNA double-strand breaks and cellular apoptosis (Figure 2).