Antibody-Based Therapies
David E. Thurston, Ilona Pysz in 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
Pat Price, Karol Sikora in Treatment of Cancer, 2014
NHL is a genetically heterogenous group of malignancies which consists of subtypes that have a marked mutational load per sample affecting a variety of different genes across different samples (e.g., DLBCL), and subtypes that have single recurrent missense mutations present at a high frequency across numerous samples with relatively few other genetic abnormalities (e.g., Waldenstroms macroglobulinaemia [WM]). The utilization of high-throughput sequencing techniques to sequence entire genomes/exomes of NHL samples has greatly increased our understanding of the molecular lesions that are associated with lymphoproliferative disorders. The genomes/exomes of multiple cases of various subtypes of lymphoproliferative disorders have now been comprehensively sequenced. The findings from these studies have identified the mechanism of dysregulation in intracellular pathways, provided insight into the clonal evolution within tumours and uncovered numerous potential targets for therapeutic intervention (Table 30.3). Mutations identified in intracellular signalling pathways are shown in Figure 30.2. An example of the implications of this technology for treatment is that a lymphoma with an activating mutation of CD79b would be expected to respond to a BTK inhibitor but not if there was also activating mutations of the downstream CARD11 gene.
Monocyte and lymphocyte membrane markers: Ontogeny and clinical significance
Gabriel Virella in Medical Immunology, 2019
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.
Management of relapsed or refractory large B-cell lymphoma in patients ineligible for CAR-T cell therapy
Published in Expert Review of Hematology, 2022
Salvatore Perrone, Paolo Lopedote, Mario Levis, Alice Di Rocco, Stephen Douglas Smith
Antibody-drug conjugates represent a major class of novel therapies in lymphoma, and offer the potential for targeted delivery of chemotherapy agents to malignant cells expressing B-cell specific surface antigens. The CD79 molecule, is a heterodimer composed of an Igα (CD79a) and Igβ (CD79b), is physically associated in the B-cell membrane with immunoglobulin. It transmits a signal after antigen binding and it appears before the pre-B-cell stage, and the CD79a chain can still be present at the plasma cell stage [59]. Polatuzumab vedotin-piiq (pola) in combination with BR was approved in 2019 by the FDA and the EMA (Figure 2) for r/r DLBCL who failed ≥2 lines of therapy, for the results of the GO29365 trial and is now incorporated in the National Cancer Care Network (NCCN) guidelines for patients in this setting [60].
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].
Polatuzumab vedotin: an investigational anti-CD79b antibody drug conjugate for the treatment of diffuse large B-cell lymphoma
Published in Expert Opinion on Investigational Drugs, 2020
Estelle Bourbon, Gilles Salles
CD79, in association with a cell surface immunoglobulin (sIg) for antigen recognition, constitutes the B-cell antigen receptor (BCR) complex that plays a critical role in B-cell maturation and activation. CD79 consists of α (CD79a) and β (CD79b) heterodimers [30–32], that functions as the signaling component of the BCR. Both subunits of CD79 contain a single extracellular Ig domain, a transmembrane domain, and an intracellular signaling domain that initiate the BCR signaling after antigen binding, ultimately leading to B-cell activation, antigen presentation, cytokine production, and cell proliferation and differentiation [33–35].
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