Thomas F. Tedder 
Duke University Medical Center, Durham, NC

B-Lymphocyte Targets for Immunotherapy: A Molecular Basis for How They Work?

B lymphocytes are the major cell lineage represented among hematologic malignancies. Normal B-lymphocyte function is regulated through cell surface molecules, including the B-cell antigen receptor. Other receptors inform B cells of their microenvironment and provide transmembrane signals that positively and negatively regulate B-cell function. These molecules are also expressed by malignant B-cell counterparts and presumably serve similar functions in transformed cells. Several of these B-cell surface receptors serve as targets for immunotherapy of malignancies, including toxin- and radio-immunoconjugates reactive with CD19, CD20 and CD22. In addition, naked anti-CD20 monoclonal antibodies (mAbs) are an accepted therapy for non-Hodgkin’s lymphoma, and naked anti-CD22 antibodies are in late-stage clinical trials. The efficacy of these therapies was identified empirically and is presumably based on the ability of the antibodies to elicit immunological recognition of the malignant cells. Effector mechanisms for anti-tumor effects include complement- and Fc receptor-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, induced apoptosis, and blocked cell cycle progression.

The CD19, CD20 and CD22 molecules have important cellular functions that critically regulate B-cell survival. Alterations in the biological functions of these receptors may also modulate malignant B-cell proliferation. For example, CD20 is a cell surface protein with hydrophobic regions that span the membrane four times. CD20 forms a complex of perhaps four CD20 molecules, which functions as transmembrane Ca2+ channels. As a regulator of transmembrane Ca2+ conductance, mAb binding to CD20 directly alters Ca2+ homeostasis and thereby abrogates cell cycle progression. This provides an attractive explanation for the therapeutic efficacy of anti-CD20 mAb treatment and suggests that small molecule agonists that mimic mAb-induced changes may also be effective therapeutics. In addition, CD20 is a member of the MS4A gene family that includes similar molecules expressed by diverse cell types. Since antibodies reactive with these proteins do not currently exist, whether these molecules will also serve as effective immunotherapy targets like CD20 is yet to be determined. CD19 is also a component of a multimolecular complex expressed by B lymphocytes that regulates intrinsic and antigen receptor-induced Src-family protein tyrosine kinase activity. Although CD19 has been an effective target for toxin- and radio-immunoconjugates, naked mAb immunotherapy has not proven useful. Nonetheless, CD19 expression levels by malignant B cells directly regulate tumor progression in mouse models, suggesting it as a potential target for therapies not involving mAbs. Like CD19, CD22 is a potent regulator of intracellular signals in B lymphocytes. In addition, CD22 serves as a receptor for broadly distributed sialic acid-bearing ligands that promote B-cell survival in vivo. Blocking the ligand-binding function of CD22 in vitro induces B- cell apoptosis in primary B cells and cell lines, which correlates with considerable therapeutic potential in vivo. Thus, optimal mAb-based therapies may be improved by considering the natural functions of their target molecules, in addition to their use as passive targets for immune effector mechanisms. Although further studies are needed to assess the relative contributions of each mechanism to the optimal killing and clearance of malignant cells, a consideration of the biological role for each receptor may allow the design or choice of appropriate targeting antibodies for eliciting maximal biological effects. More important however is that an understanding of the biology of these therapeutic targets may explain why they are not uniformly successful.