B-cell maturation antigen (BCMA), B-cell activating factor receptor (BAFF-R), and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACT) promote B-cell survival at distinct stages of development by engaging a proliferation-inducing ligand (APRIL) and/or BAFF (B-cell activating factor). Dysregulated signaling can promote B-cell survival and proliferation, causing autoimmunity and neoplasia. For a review, see Rickert, et al., Immunological Reviews 2011, Vol. 244: 115-133.
BAFF and APRIL exhibit structural similarity and overlapping yet distinct receptor binding specificity. BAFF and APRIL bind BCMA, but the APRIL:BCMA interaction is of higher affinity, whereas BAFF-R only binds BAFF with high affinity. The negative regulator TACI binds to both BAFF and APRIL with similar affinity. BCMA expression in the B cell lineage is restricted to germinal center B cells, memory B cells (in humans), and plasma cells. BCMA is a receptor for BAFF and APRIL engagement on bone marrow plasma cells, although TACI is also expressed on these cells. The survival of long-lived plasma cells does not require BAFF but is dependent upon APRIL.
BCMA expression is highly restricted to plasma cells. Multiple myeloma is caused by a clonal expansion of malignant plasma cells. By 2020, the total number of incident cases of multiple myeloma (MM) in the major markets will increase from 46,400 to 55,300. Newly diagnosed cases of myeloma are similarly distributed between three disease stages with stage 1, 2 and 3 accounting for about 33% of the diagnosed cases each. In the US, approximately 20,500 people are diagnosed with multiple myeloma each year and almost 11,000 MM patients die each year. Despite advances in therapy, multiple myeloma remains an incurable disease, see Jemal A, et al. CA Cancer J Clin. 2008; 58:71-96; Kyle R A, et al. Mayo Clin Proc. 2003; 778:21-33; Bergsagel D E, et al. Blood. 1999, 94:1174-1182.
USPTO Backgrounds
USPTO Backgrounds