Bispecific Antibodies Targeting CD3 and Survivin

Introduction of CD3

CD3, also recognized as the T cell receptor (TCR) associated molecule CD3 complex or T3 antigen, is a cell surface molecule crucial for T cell function. Comprising five distinct polypeptide chains—CD3γ, CD3δ, CD3ε, CD3ζ, and CD3η—it forms a hetero-octamer alongside TCRα and TCRβ chains. Predominantly expressed on T cells and encoded by the TCR gene complex, CD3 serves as a signal transduction molecule for TCR, playing a pivotal role in T cell activation, proliferation, and differentiation. Notably, CD3 emerges as a potential therapeutic target for diseases such as leukemia, lymphoma, malignant melanoma, and others.

Introduction of Survivin

Survivin, also identified as baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5), is a human protein encoded by the BIRC5 gene. As a member of the inhibitor of apoptosis (IAP) family, the survivin protein, consisting of 142 amino acids, features a BIR domain and a C-terminal coiled-coil dimerization domain. Its primary expression occurs in dividing cells, encoded by the BIRC5 gene. Survivin's fundamental biological functions encompass apoptosis inhibition, cell cycle regulation, participation in microtubule formation, and chromosome segregation. It emerges as a potential therapeutic target for diseases including solid tumors, leukemia, rheumatoid arthritis, among others.

Fig.1 Survivin Crystallization as a Homodimer (Wheatley SP, 2019)

Signaling Pathways Involved in Bispecific Antibodies Targeting CD3 and Survivin

Bispecific antibodies (BsAbs) designed to target CD3 and Survivin exhibit potent anti-tumor effects through two distinct mechanisms. The first mechanism involves redirecting T cell killing of tumor cells, while the second involves blocking the Survivin signaling pathway and inducing tumor cell apoptosis.

Mechanism 1(redirecting T cell killing of tumor cells): BsAbs play a pivotal role in this mechanism by simultaneously recognizing and binding CD3 on T cells and Survivin on tumor cells. This dual recognition brings the two cell types into close proximity, activating downstream signaling pathways of the TCR/CD3 complex in T cells, such as Ras/ERK, PI3K/Akt, and NF-κB. These signaling pathways stimulate T cells to release cytokines (e.g., IL-2, IFN-γ, TNF-α) and cytotoxic molecules (e.g., perforin and granzyme), leading to the effective killing of tumor cells.

Mechanism 2 (blocking survivin signaling pathway and inducing tumor cell apoptosis): BsAbs target Survivin on tumor cells, disrupting its interaction with other proteins (e.g., XIAP, Caspase-3, and Caspase-9). This interference compromises the stability and function of Survivin, preventing its effective inhibition of apoptosis signaling pathways, including intrinsic and extrinsic apoptosis pathways. Consequently, the activation of Caspase family proteins triggers the apoptosis program in tumor cells.

Clinic Status of Bispecific Antibodies Targeting CD3 and Survivin

Despite the promising potential, the clinical application of BsAbs targeting CD3 and Survivin is still in its early stages. Only a few BsAbs have gained approval or are currently undergoing clinical trials. A notable example is ABBV-184, a T cell receptor/CD3 bispecific T cell engager (TCE). ABBV-184, currently in phase III clinical trials, specifically binds Survivin-derived peptides expressed on HLA-A*02:01 positive tumor cells, activating T cells to eliminate tumor cells. Although not yet on the market, ABBV-184 is showing promise in treating c-Met overexpression, EGFR wild-type, locally advanced/metastatic non-small cell lung cancer, with the clinical trial anticipated to conclude in 2026.

Fig.2 Tumor Response to ABBV-184 Treatment (Chervin AS, 2023)

Table 1. Summary of ABBV-184