CD79 is a transmembrane protein that binds to the B cell receptor (BCR) to form a complex and generate signals upon antigen recognition by the BCR. CD79 is composed of two distinct peptide chains, CD79a ( Igα ) and CD79b (Igβ), which form a heterodimer on the B cell surface through a disulfide bond and participate in signal transduction on B cells. CD79 is expressed in mature B cells and lymphoma cells and has a broad mechanism of action for killing B cell tumors.
CD79 structure and function:
CD79 is a transmembrane protein composed of two subunits, CD79a and CD79b. CD79a and CD79b have similar structures, each containing an extracellular domain, an intracellular domain, and a transmembrane domain. They are bound together by disulfide bonds formed between cysteine residues in their extracellular domains.
(Data source: Su Q, et al. Science. 2022)
The extracellular, intracellular, and transmembrane regions of CD79 have distinct functions on B cells. The intracellular domain of CD79a/CD79b possesses an immunoreceptor tyrosine-based activation motif (ITAM), consisting of 26 amino acid residues and containing two key tyrosine residues. ITAM tyrosine residues can be phosphorylated by the Src family of kinases and are directly involved in BCR signaling. Protein - protein interactions between the transmembrane domains of CD79a/CD79b play a crucial role in BCR assembly and signaling. The extracellular domain of CD79a/CD79b interacts with immunoglobulins, promoting BCR assembly and stability, regulating IgM trafficking and surface levels, and mediating proper BCR assembly. These functions contribute to maintaining BCR functionality. The CD79a/CD79b heterodimer is one of the key regulators of BCR signaling and B cell fate.
(Data source: Tkachenko A, et al. Int J Mol Sci. 2023)
CD79 signaling pathway:
The CD79a/CD79b heterodimer determines BCR internalization through its ubiquitination and ITAM phosphorylation. Monophosphorylation of the CD79 ITAM recruits Lyn, while dual phosphorylation docks SYK, further activating BTK and PLCγ2, thereby activating downstream NF-κB and PI3K/AKT signaling. The CD79a/CD79b heterodimer also mediates synergistic signaling from CD19, BAFFR, MHC class II, and TLR9, and is regulated by KLHL14 and TRAF3 (tumor necrosis factor receptor (TNFR)-associated factor 3). The CD79a/CD79b heterodimer can also bind to MHC class II and contribute to its downstream signaling. CD79b, along with other proteins involved in proximal BCR signaling (SYK and BTK), interacts with TRAF3, a negative regulator of BCR signaling. Therefore, this interaction leads to reduced activation of the non-canonical NF-κB and MAPK/ERK pathways without affecting canonical NF-κB and PI3K/AKT signaling.CD79a and CD79b play crucial roles in signaling pathways and regulation in normal B cells and are essential for maintaining B cell function and immune responses.
(Data source: Tkachenko A, et al. Int J Mol Sci. 2023)
CD79 target drugs
Polatuzumab vedotin, an anti-CD79b antibody-drug conjugate (ADC), was approved by the FDA in June 2019 for the treatment of relapsed/refractory diffuse large B-cell lymphoma. Polatuzumab vedotin binds to CD79 and is internalized within cells. Lysosomal proteases then release MMAE, which binds to microtubules, inhibiting cell division and inducing apoptosis.
(Data source: Burke JM, et al. Expert Rev Clin Pharmacol. 2020)
Polatuzumab vedotin was approved for marketing by the National Medical Products Administration in January 2023. It is used in combination with rituximab, cyclophosphamide, doxorubicin and prednisone to treat adult patients with previously untreated DLBCL; and in combination with bendamustine and rituximab to treat adult patients with relapsed or refractory DLBCL who are not suitable for hematopoietic stem cell transplantation.
