Bispecific Antibodies Targeting CD3 and CD19

Introduction to CD3

CD3 is a protein complex that constitutes a part of the T cell receptor (TCR) on the surface of T cells. It comprises four distinct polypeptide chains: CD3γ, CD3δ, CD3ε and CD3ζ, each containing one or more immunoreceptor tyrosine-based activation motifs (ITAMs). CD3 plays a crucial role in T cell activation and signal transduction by transmitting signals from the TCR to intracellular pathways such as Ras-MAPK, PI3K-Akt, and NF-κB. While primarily expressed in mature T cells, CD3 is also found in some immature thymocytes and natural killer (NK) cells. It represents a potential target for immunotherapy against various diseases and tumors, influencing the function and specificity of T cells. For instance, bispecific antibodies targeting CD3 and another antigen can redirect T cells to eliminate tumor cells or infected cells.

Introduction to CD19

CD19 is a protein forming part of the B cell co-receptor complex on the surface of B cells. Comprising a single transmembrane polypeptide chain with two extracellular immunoglobulin-like domains and a cytoplasmic tail with nine tyrosine residues, CD19 plays a pivotal role in B cell development, activation, and signal transduction. It enhances signals from the B cell receptor (BCR) to intracellular pathways like PLCγ2-Ca2+, PI3K-Akt, and NF-κB. While predominantly expressed on all stages of B cells except plasma cells, CD19 is a potential target for immunotherapy against various B cell-derived malignancies, including acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM). For instance, bispecific antibodies targeting CD19 and another antigen can recruit T cells or NK cells to eliminate tumor B cells or induce antibody-dependent cellular cytotoxicity (ADCC).

Signaling Pathways Involved in Bispecific Antibodies Targeting CD3 and CD19

Bispecific antibodies (BsAbs) are artificial antibodies with two different antigen-binding sites that can simultaneously target two different antigens or two different epitopes on the same antigen. BsAbs targeting CD3 and CD19 (BsAb-CD3/CD19) represent a novel form of immunotherapeutic drug developed using BsAb technology. These antibodies can recognize and connect CD3 on T cells and CD19 on B cells, achieving T cell-mediated B cell-specific killing. BsAb-CD3/CD19 initially binds to CD3 on T cells, causing phosphorylation of the ζ chain in the TCR/CD3 complex and activating downstream signal transduction molecules, such as ZAP-70, LAT, PLC-γ1, etc. These molecules further activate several signaling pathways, such as the Ras-MAPK pathway, the PI3K-Akt pathway, the NF-κB pathway, etc., leading to T cell activation, proliferation and cytokine release. At the same time, BsAb-CD3/CD19 binds to CD19 on B cells, causing CD19 phosphorylation and activating downstream signal transduction molecules such as Lyn, Syk, PI3K, etc., leading to B cell activation, proliferation and antibody secretion. Due to the mediation of BsAb-CD3/CD19, a tight immunological synapse forms between T cells and B cells, allowing T cells to induce B cell apoptosis by releasing effector molecules such as perforin and granzyme. In this way, BsAb-CD3/CD19 achieves a therapeutic effect on B cell-related diseases.

Clinical Status of Bispecific Antibodies Targeting CD3 and CD19

The clinical status of bispecific antibodies targeting CD3 and CD19 is promising, demonstrating significant efficacy and safety in various B cell-derived malignancies. To date, the FDA has approved only one bispecific antibody targeting CD3 and CD19, namely blinatumomab (Blincyto®). Blinatumomab, based on the bispecific T-cell engager platform, is a single-chain variable fragment (scFv) antibody consisting of two scFvs recognizing CD3 and CD19, respectively, connected by a short peptide without an Fc structure. FDA approval in 2014 covers its use in the treatment of relapsed or refractory B cell precursor acute lymphoblastic leukemia (B-ALL) and B cell precursor ALL in the first or second complete remission with minimal residual disease (MRD). Blinatumomab has also gained approval in Europe, Japan, and China.

Fig.1 Blinatumomab: Structure and mechanism of action. (Nagorsen D, 2011)

Several other bispecific antibodies targeting CD3 and CD19 are currently in clinical trials, primarily developed by Roche/Genentech, Janssen, Merck, and other companies or research institutions. These antibodies are mainly intended for the treatment of B cell-derived malignancies, including B-ALL, non-Hodgkin lymphoma (NHL), and multiple myeloma (MM).

Table 1. Some of the bispecific antibodies targeting CD3 and CD19 in clinical trials

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