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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Polatuzumab vedotin is based on a humanized monoclonal antibody targeting CD79b present on the surface of B cells. The antibody is conjugated to the MMAE payload through a protease-cleavable peptide (i.e., valine-citrulline) linker using maleimide chemistry, and has an average DAR of 3.5 (Figure 7.34). Structure of polatuzumab vedotin (Polivy™) (Figure from Li, D, Lee, D, Dere, RC, et al. Evaluation and use of an anti-cynomolgus monkey CD79b surrogate antibody–drug conjugate to enable clinical development of polatuzumab vedotin. Br J Pharmacol. 2019; 176: 3805–3818. https://doi.org/10.1111/bph.14784. Copyright © 2019 Genentech Inc. British Journal of Pharmacology).
Non-Hodgkin Lymphoma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Piers Blombery, David C. Linch
Patients who are refractory to salvage chemotherapy or who have relapsed post-ASCT have a very poor prognosis with conventional therapy, and the treatment is generally palliative. There is little benefit in re-treatment with an alternative conventional regimen, and therefore non-chemotherapy based novel agents tend to be utilized in this group, for example BTK inhibitors, lenalidomide, and antibody-drug conjugates such as polatuzumab vedotin (anti-CD79B). However, one of the most promising approaches in this group is the use of chimeric antigen receptor T (CART) cells. Whilst this is a rapidly evolving field, the approach generally involves collection of autologous T-lymphocytes from the patient using apheresis and then transduction of these T-cells with a chimeric T-cell receptor which has specificity for an antigen expressed on the DLBCL surface (most commonly CD19). These engineered T-cells are then reinfused to the patient and induce immune-mediated killing of tumor cells. Response rates in R/R DLBCL with CART cell therapy are high (>80%) with complete remissions observed in approximately 30%–50% in early clinical trials, making this one of the most effective treatments of relapsed disease.42 Moreover, whilst CART cell therapy may have significant toxicity (cytokine release syndrome, neurotoxicity), the field is still maturing and improvements in receptor structure, antigen specificity, toxicity, manufacturing times, and cost are expected to make CART cell therapy one of the most important recent therapeutic developments in DLBCL (and indeed many other lymphomas).
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
The B cell receptor (BCR) complex is constituted by sIg associated with CD79a/Igα) and CD79b/Igβ (Figure 10.3). Antigen recognition occurs though the sIg, whereas Igα and Igβ mediate signal transduction. After antigen binding, the recruitment of tyrosine kinase to the cytoplasmic domains of Igα and Igβ initiates the activation cascade. The major kinase that is recruited to the BCR complex is Bruton's tyrosine kinase (Btk). Congenital Btk deficiency is associated with a block in B-cell differentiation, demonstrating that signals delivered through the fully assembled BCR and associated kinases are necessary for B cell development during ontogeny.
Polatuzumab vedotin for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma
Published in Expert Opinion on Biological Therapy, 2021
Mary-Kate Malecek, Marcus P. Watkins, Nancy L. Bartlett
Polatuzumab vedotin (Genentech, South San Francisco, CA, USA) is an ADC comprised of an anti-CD79b monoclonal antibody conjugated to monomethyl auristatin (MMAE), a microtubule-disrupting cytotoxin (Box 1). CD79b is a signaling component of the B cell receptor (BCR) complex and is expressed almost exclusively on normal and malignant B cells [53]. CD79a and CD79b expression precedes CD20 expression and disappears in later stages of B cell ontogeny. BCR cross-linking triggers signaling, targeting it to the lysosome-like major histocompatibility complex class II positive compartment. This allows ADC internalization, lysosomal degradation of the linker, and release of the drug only in the targeted cells. CD79b is expressed in DLBCL, mantle cell lymphoma, Burkitt lymphoma, and follicular lymphoma , and is, therefore, an appealing target for the development of novel therapeutics [54].
The latest developments with anti-CD20 monoclonal antibodies in chronic lymphocytic leukemia
Published in Expert Opinion on Biological Therapy, 2018
Mitchell Evers, Margot Jak, J. H. W. Leusen
Over the last two decades, many attempts have been made to discover additional antigens, such as CD52, CD79b, and CD19, to improve therapy for B-cell malignancies. However, CD20 is still the predominant target for a multitude of oncological indications, and there are several reasons why this might be the case. First, the stage of CD20 expression on the B-cell lineage is ideal for antibody targeting purposes. CD20 expression is established just before membranous IgM heavy-chain expression during the pro-B-cell stage and is lost immediately after differentiation to antibody-secreting plasma cells, minimizing the chance for stem cell depletion or infection due to loss of humoral immunity [41]. Furthermore, CD20 is not blocked by a natural ligand and is not extracellularly post-translationally modified, enabling the entire amount of CD20 for antibody interaction [42]. Although murine CD20 shares 73% amino acid homology with human CD20, it is not recognized by clinically used antibodies. Therefore, in vivo testing of these antibodies is relatively straightforward without the interference of binding to mouse B cells [43]. Next to expression on healthy B cells, high CD20 expression is retained on the majority of B-cell lymphomas, although expression levels differ between subtypes. The relatively mature CLL cells have a lower CD20 expression compared to other B-cell malignancies [44]. Finally, the side effects of anti-CD20 therapy, such as neutropenia and reduced IgM levels, are well-known and can be kept adequately under control [45].
Novel insights into the pathogenesis of molecular subtypes of diffuse large B-cell lymphoma and their clinical implications
Published in Expert Review of Clinical Pharmacology, 2019
The important role of BCR receptor signaling in the biology of ABC DLBCLs has been shown by identification of recurrent mutations in this pathway. In roughly 20% of ABC DLBCLs, mutations of CD79B, most frequently located in the critical ITAM motif, can be detected [29]. The described CD79B mutations in ABC lymphomas seem to lead to an enhanced expression of B-cell receptors (but not to the described formation of clusters), possibly due to a disturbed B-cell receptor internalization. Besides, CD79B mutations minimize the inhibitory effect on BCR signaling by the SFK LYN [29].