Identification of Unique Molecular Heterogeneity of Human CD79, the Signaling Component of the Human B Cell Antigen Receptor (BCR), and Synergistic Potentiation of the CD79-targeted Therapy of B Cell Tumors by Co-targeting of CD79a and CD79b

We identified unique molecular heterogeneity of CD79 of human B cell antigen receptor (BCR) that may open a new approach to the ongoing CD79b-targeted therapy of B cell tumors. The primary purpose of the present study is to gain new information valuable for the enhanced CD79-targeted therapy. The molecular heterogeneity of CD79 was identified by sequential immunoprecipitation of BCR by use of anti-CD79b monoclonal antibody (mAb) SN8 and anti-CD79a mAb SN8b. SN8 is the antibody component of polatuzumab vedotin, an anti-CD79b antibody drug conjugate, that has been widely used for therapy of diffuse large B-cell lymphoma (DLBCL). The sequential immunoprecipitation shows that anti-CD79b mAb will be able to react only with a subgroup of CD79 molecules while anti-CD79a mAb will react with another subgroup of CD79 molecules; CD79 is a disulfide-linked heterodimer of CD79a and CD79b. Therapeutic study of SCID mice bearing human B-cell tumor shows synergistic potentiation by co-targeting CD79b and CD79a. Furthermore, simultaneous targeting of PD-1 strongly potentiates CD79a/CD79b-targeted therapy of B cell tumors. Flow cytometry analyses of CD79a/CD79b on malignant B cells of patients may provide a method for selection of the candidate patients for the CD79a/CD79b dual targeting therapy.