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B-Cell Surface Proteins
B-cell biology and its role in cancer is another area of intensive research at Genentech BioOncology. B cells are a fundamental component of the body's immune system. However, like most cells in the body, B cells can become cancerous — leading to diseases such as non-Hodgkin's lymphoma.20 Identifying antigens found on the surface of cancerous B cells allows these cells to be "targeted," either by generating antibodies to these proteins, thereby marking them for destruction by the body's own immune system, or by using antibodies to deliver cytotoxic drugs directly.20-22
B-cell biology MOA animation
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Antibodies recognize and bind to proteins found on the surface of malignant B cells.
This may lead to initiation of innate cell death programs, identification and destruction of the malignant cell by killer T cells in a process called antibody-dependent cell-mediated cytotoxicity, and facilitation of the binding of the "complement" system — proteins that destroy the cell membrane integrity — in a process called complement-dependent cytotoxicity.23
Cell-surface proteins such as CD20 and CD40 are highly expressed on most B-cell hematologic malignancies, and these antigens represent key targets in malignancies including non-Hodgkin's lymphoma, multiple myeloma, and chronic lymphocytic leukemia.21,23,24 Genentech is developing two antibodies, one that targets CD20, and the other, CD40.
A 3rd-generation anti-CD20 monoclonal antibody is in clinical development. This Fc-engineered, humanized antibody binds to CD20 on the surface of B cells and targets them for destruction through several possible mechanisms, including increased CD20 and FcγRIIIA binding affinity, increased antibody-dependent cell-mediated cytotoxicity (ADCC), and increased complement-dependent cytotoxicity (CDC).
Genentech BioOncology, in collaboration with Seattle Genetics Inc, is developing anti-CD40: a humanized monoclonal antibody that targets CD40 on the surface of B cells. In preclinical studies, anti-CD40 has demonstrated antibody-dependent cellular cytotoxicity and may induce apoptosis, resulting in inhibition of B-cell tumor growth.21,25 Anti-CD40 is currently in clinical development for patients with a range of hematologic malignancies.
Journal Articles
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US Department of Health and Human Services. What you need to know about™ Non-Hodgkin's Lymphoma. NIH Publication No. 05-1567. April 2005.
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Tai YT, Catley LP, Mitsiades CS, Burger R, et al. Mechanisms by which SGN-40, a humanized anti-CD40 antibody, induces cytotoxicity in human multiple myeloma cells: clinical implications. Cancer Res. 2004;64:2846-2852.
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Capizzi RL. Targeted radio-immunotherapy with Bexxar produces durable remissions in patients with late stage low grade non-Hodgkin's lymphomas. Trans Am Clin Climatol Assoc. 2004;115:255-272.
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Riley JK, Sliwkowski MX. CD20: a gene in search of a function. Semin Oncol. 2000;27:17-24. US Department of Health and Human Services. What you need to know about™ Non-Hodgkin's Lymphoma. NIH Publication No. 05-1567. April 2005.
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Funakoshi S, Longo DL, Beckwith M, et al. Inhibition of human B-cell lymphoma growth by CD40 stimulation. Blood. 1994;83:2787-2794.
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Kelley SK, Gelzleichter T, Xie D, et al. Preclinical pharmacokinetics, pharmacodynamics, and activity of a humanized anti-CD40 antibody (SGN-40) in rodents and non-human primates. Br J Pharmacol. 2006;148:1116-1123.