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DISCOVERY OF THE CD20 ANTIGEN

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CD20 was one of many lymphocyte surface antigens that were identified in a flurry of work in the 1970–1980s [1, 2]. The prototype antigen, B1, was found to be specific for B cells, and distinct from other B-cell markers such as surface immunoglobulin. Anti-B1 and other anti–CD20 antibodies promptly came into wide use as diagnostic agents and research tools. Only later was attention paid to the potential of CD20 as a therapeutic target.

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CD20 AND OTHER GENE FAMILY MEMBERS

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The gene that encodes CD20 is in the region of chromosome 11q12–q13.1 [3]. CD20 is a member of a family of proteins collectively described as the MS4A family (membrane-spanning 4-domain family, sub-family A). Besides CD20, the family members that are best characterised are the β chain of the high-affinity receptor for IgE (FcεRIβ), and HTm4 [4–7]. Both of these proteins are also encoded by genes in the same region of chromosome 11.

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Besides structural similarity and limited (up to about 30%) amino acid sequence homology, many MS4A family members share functional features that in a general way relate to immune function. FcεRIβ is expressed by mast cells and basophils. HTm4 is expressed by haematopoietic cells of lymphoid and myeloid origin. Other family members are expressed mainly in lymphoid tissues including the thymus and spleen [5]. Some of them appear to function as components of a calcium channel.

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ANATOMY OF CD20

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CD20 is a 33 to 37-kDa non-glycosylated phosphoprotein with four transmembrane regions, a relatively short extracelluar loop of 43–44 amino acids, and cytoplasmic N- and C-terminal regions [8–11]. The molecule is phosphorylated at a basal level in resting B cells, and becomes heavily phosphorylated following activation in both normal and malignant B cells.

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Figure 4.1

Schematic diagram of CD20. The extracellular portion (amino acid residues 142–184) is the site of attachment for most monoclonal antibodies. The alanine residue at 170 and proline at 172 are critical for anti-CD20 antibody binding. Adapted from [8].

Graphic Jump Location
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Numerous antibodies have been developed that recognise different epitopes of CD20. Most recognise the extracellular portion of CD20, including B1 and other antibodies that were developed early, such as 1F5 and 2H7. Some anti-CD20 antibodies recognise only assembled multimeric complexes of CD20 [12]. The level of expression of the CD20 epitope recognised by the FMC7 antibody is dependent on the cell membrane cholesterol content [13].

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The amino acids at positions 170 (alanine) and 172 (proline) of CD20 are critical determinants for binding of the anti-CD20 antibodies that recognise extracellular epitopes [12].

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L26 is a notable anti-CD20 antibody because it recognises an intracellular epitope that is preserved ...

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