Bispecific Antibodies Targeting CD3 and CEA

Introduction to CD3

CD3 is a part of the T cell receptor complex (TCR), consisting of four polypeptide chains: CD3γ, CD3δ, CD3ε and CD3ζ, which are expressed on all mature T cells. CD3 is a key molecule for T cell activation and signal transduction. When the TCR recognizes and binds to an antigen, the immunoreceptor tyrosine-based activation motifs (ITAMs) on the CD3 chains are phosphorylated, which recruit and activate a series of signal molecules, such as ZAP70, LAT, PLCγ and so on. CD3 acts as a modulator of T cell effector functions and plays an important role in various immune-related diseases, such as autoimmune diseases, transplant rejection, infectious diseases and so on. At the same time, CD3 is also an important target for tumor immunotherapy. By using BsAbs that bind to both CD3 and tumor-associated antigens (TAAs), T cells can be directed to tumor cells and kill them.

Introduction to CEA

CEA stands for carcinoembryonic antigen, also known as CEACAM5 or CD66e, a transmembrane glycoprotein belonging to the CEACAM family, encoded by the CEACAM5 gene. CEA has low or absent expression in normal adult tissues, mainly present in the placenta and fetal liver. However, in various malignant tumors, such as colorectal cancer, breast cancer, pancreatic cancer, and more, CEA expression is significantly elevated and associated with tumor differentiation, invasiveness, and prognosis. CEA has multiple biological functions, including regulating cell adhesion, enhancing tumor cell migration and invasion, and inhibiting the immune system's recognition and clearance of tumor cells. Therefore, CEA is a clinically significant tumor marker and therapeutic target.

Signaling Pathways Involved in BsAbs Targeting CD3 and CEA

BsAbs targeting CD3 and CEA exert anti-tumor effects through two main mechanisms: first, by recruiting and activating T cells, inducing cytotoxic death of tumor cells; second, by blocking the interaction between CEA and other molecules on tumor cells or the matrix, inhibiting tumor cell growth and metastasis. When BsAbs bind to both CD3 and CEA simultaneously, they trigger the CD3 signaling pathway in T cells, leading to T cell proliferation, differentiation and release of effector molecules such as cytokines (such as IFN-γ, TNF-α and so on), perforin and granzyme. These effector molecules can directly or indirectly kill tumor cells, or alter the tumor microenvironment, enhancing the immune response. On the other hand, BsAbs can also interfere with the function of CEA on tumor cells, inhibiting tumor development. CEA can form homotypic or heterotypic dimers or oligomers with identical or different molecules, participating in various signaling pathways, such as Wnt/β-catenin, PI3K/Akt, MAPK/ERK and more. These signaling pathways promote tumor cell proliferation, survival, migration and invasion. Therefore, BsAbs can block CEA dimerization or oligomerization, inhibiting the activation of these signaling pathways and thereby inhibiting tumor growth and metastasis.

Clinical Progress of BsAbs Targeting CD3 and CEA

There are two BsAbs targeting CD3 and CEA that are highly likely to be approved by the FDA, namely MEDI-565 (MT111) and Cibisatamab (RG7802).

Table 1. Comparison of MEDI-565 (MT111) and Cibisatamab (RG7802)

In addition to the above-mentioned BsAbs, there are also several BsAbs targeting CD3 and CEA that are in preclinical or clinical development, such as RG7800 (RO6958688), AMG 160, JNJ-61186372 (JNJ-6372), REGN5678 and so on. These BsAbs are mainly developed by pharmaceutical companies or research institutions, such as Roche, Amgen, Johnson & Johnson, Regeneron and so on. They have different formats and properties, such as full-length IgG-like BsAbs, BiTEs, DVD-IgBs and so on. They are mainly aimed at various types of CEA-positive solid tumors, such as colorectal cancer, gastric cancer, pancreatic cancer and so on.

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