T cell receptors (TCRs) are protein complexes formed by six different polypeptides. The CD3 (cluster of differentiation 3) complex is part of the T-cell receptor (TCR) complex and is composed of two CD3ε, one CD3γ, one CD3δ, and two CD3ζ chains.1,2 CD3 complex ensures signal transduction and plays an important role in T-cell activation.1-3
A bispecific antibody approach may allow for binding to targets on malignant cells, while simultaneously binding to CD3 on T cells, inducing activation and cytotoxic activity of T cells enabling lysis of target-expressing malignant cells.1,5
CD3 bispecific antibodies (bsAb) induce the activation and cytotoxic activity of effector T cells enabling lysis of target-expressing malignant cells.1,3,5
- CD3 bsAb activate T cells by binding CD3 on T cells and a tumor-associated antigen (TAA) on the cancer cells. Consequently, all available T cells can bind to target-expressing cells irrespective of the peptide/major histocompatibility complex (MHC) specificity of their T-cell receptor (TCR). 1,3
- Activation of the TCR-CD3 complexes leads to the formation of a cytolytic synapse between the T cell and the tumor cell which results in the release of perforin and granzymes and subsequent tumor cell death by apoptosis.1
T-cell redirection with bispecific antibodies in which one binding arm recognizes a tumor antigen and the other binding arm recognizes CD3 on T-cells.
CD3 bsAbs in clinical trials either lack an Fc region or contain an engineered Fc domain to minimize interaction with Fc receptors.1,3
- The presence of an Fc domain increases the in vivo half-life through binding to the neonatal Fc receptor.3
A key CD3 bsAb development consideration is a need for a format that either significantly limits or eliminates cyokine release syndrome (CRS), since CRS appears to be dose-limiting in most cases for this class of molecules1
IMPLICATIONS IN CANCER
Immunotherapy of cancer with CD3 bsAb is a fast developing field, and multiple TAAs are under evaluation for both hematological and solid tumor malignancies with many different CD3 bs Abs in clinical development.3,5
- The idea of using the cytotoxic capacity of T cells through CD3 bsAb to kill tumor cells dates back to 1980’s.3,6
TUMOR-ASSOCIATED ANTIGEN TARGETS
CD20 (cluster of differentiation 20) on B-cells is a clinically well-validated target that is expressed in a wide variety of B-cell malignancies with limited normal tissue expression beyond B cells.7,8
BCMA (B cell maturation antigen) is exclusively expressed on the surface of plasmablasts and differentiated plasma cells (PCs), but not on memory B cells, naïve B cells, CD34+ hematopoietic stem cells, and other normal tissue cells. In multiple myeloma (MM), expression of BCMA is significantly increased on malignant versus normal PCs.4
- In normal physical functions, BCMA supports survival of long-lived PCs, production of antibodies and class switch of immunoglobulin.4
- In MM, overexpression of BCMA promotes proliferation and survival of MM cells, is associated with an immunosuppressive bone marrow (BM) microenvironment, and increased levels of soluble BCMA (sBCMA) are associated with disease progression and poorer outcomes.4
- Strohl WR, Naso M. Bispecific T-Cell Redirection versus Chimeric Antigen Receptor (CAR)-T Cells as Approaches to Kill Cancer Cells. Antibodies (Basel). 2019 Jul 3;8(3):41.
- Alcover A, et al. Cell Biology of T Cell Receptor Expression and Regulation. Annu. Rev. Immunol. 2018. 36:85–107.
- Benonisson H, et al. CD3-Bispecific Antibody Therapy Turns Solid Tumors into Inflammatory Sites but Does Not Install Protective Memory. Mol Cancer Ther. 2019;18(2):312-322.
- Cho SF, et al. Targeting B cell maturation antigen (BCMA) in multiple myeloma: potential uses of BCMA-based immunotherapy. Frontiers in immunology. 2018 Aug 10;9:1821.
- Labrijn AF, Janmaat ML, Reichert JM, Parren PWHI. Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 2019 Aug;18(8):585-608.
- Staerz UD, Kanagawa O, Bevan MJ. Hybrid antibodies can target sites for attack by T cells. Nature. 1985 Apr 18-24;314(6012):628-31.
- Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study. Lancet. 2021;398(10306):1157-1169.
- Engelberts PJ, et al. DuoBody-CD3xCD20 induces potent T-cell-mediated killing of malignant B cells in preclinical models and provides opportunities for subcutaneous dosing. EBioMedicine. 2020 Feb;52:102625.