Bispecific Antibodies Targeting CD3 and DLL3

Introduction of CD3

CD3, short for cluster of differentiation 3, is a pivotal component known as the T-cell co-receptor or T3 antigen. Comprising five distinct polypeptide chains (α, β, γ, δ, and ε), CD3 is prominently expressed on the cell membrane of mature T cells. The genetic blueprints for CD3 are nestled on human chromosome 11 (α, δ, and ε chains) and chromosome 7 (β and γ chains). Functionally, CD3 collaborates with the T cell receptor (TCR) to transmit signals for antigen recognition, thereby instigating T cell proliferation, differentiation, and effector responses. With its potential implications in autoimmune diseases, organ transplant rejection, infectious diseases, and cancer, CD3 emerges as a promising therapeutic target.

Introduction of DLL3

DLL3, denoting Delta-like canonical Notch ligand 3 or Delta-like protein 3, is a single-pass, type I transmembrane protein belonging to the DSL family (Delta/Serrate/Lag2). Encoded by the DLL3 gene situated on human chromosome 19, DLL3 comprises 619 amino acids, with a molecular weight of approximately 50.4 kDa. DLL3 plays a crucial role in neural tube development and neuronal differentiation, being expressed during both embryonic and adult stages. Functionally, DLL3 inhibits the Notch signaling pathway by binding to various Notch receptors without activating the pathway. Its unique characteristic of interfering with canonical ligand binding positions DLL3 as an ideal target for diseases, particularly in the context of tumor therapy. Highly expressed in various tumors, notably in small cell lung cancer (SCLC), DLL3's minimal presence in normal tissues makes it an attractive candidate for therapeutic intervention, particularly due to its ability to distinguish tumor cells from their normal counterparts.

Signaling Pathways Involved in Bispecific Antibodies Targeting CD3 and DLL3

Bispecific antibodies targeting CD3 and DLL3 can exploit T cell-mediated immune response to kill tumor cells. These antibodies can simultaneously recognize CD3-positive T cells and DLL3-positive tumor cells, forming an immunological synapse, triggering T cell activation and proliferation, and releasing cytokines and toxins to eliminate tumor cells.

Fig.1 Schematic Diagram of the Primary Structure of the DLL3 Bispecific Antibody

Bispecific antibodies targeting CD3 and DLL3 exert a profound impact on the Notch signaling pathway, effectively hindering tumor cell growth and metastasis. The Notch signaling pathway, a conserved cell-to-cell communication mechanism, involves four Notch receptors (Notch1-4) and five ligands (Jagged1-2 and DLL1-4). While playing a crucial role in normal cell development and differentiation, the Notch signaling pathway often experiences abnormal activation or inhibition in tumor cells, leading to disruptions in cell proliferation, apoptosis, angiogenesis, stem cell maintenance, and epithelial-mesenchymal transition. DLL3, classified as a non-canonical Notch ligand, binds to Notch receptors without triggering pathway activation. Instead, it impedes the binding of canonical ligands, resulting in the inhibition of the Notch signaling pathway. Consequently, the targeted approach of utilizing bispecific antibodies against DLL3 holds promise in further reducing the activity of the Notch signaling pathway.

Clinic Status of Bispecific Antibodies Targeting CD3 and DLL3

Bispecific antibodies targeting CD3 and DLL3 represent an innovative immunotherapy strategy, with several candidates currently advancing through various stages of clinical trials or gaining marketing approval. These groundbreaking drugs predominantly focus on SCLC, a malignancy characterized by high DLL3 expression and considerable resistance to conventional treatments.

Table 1. Clinical Trials of Bispecific Antibodies Targeting CD3 and DLL3

Fig.2 AMG 757 - Transiently Connecting DLL3-Positive Cells to CD3-Positive T Cells (Owen DH, 2019)