CD3 x CD20 BISPECIFICS
OVERVIEW
T cell receptors (TCRs) are protein complexes formed by six different polypeptides. The cluster of differentiation 3 (CD3) complex is part of the TCR complex and is composed of two CD3ε, one CD3γ, one CD3δ, and two CD3ζ chains.1,2 The CD3 complex ensures signal transduction and plays an important role in T cell activation.1-3
Cluster of differentiation 20 (CD20) is a membrane-embedded surfaced molecule that plays a role in the development and differentiation of B-cells into plasma cells.4 CD20 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.5,6
A CD3 x CD20 bispecific antibody simultaneously binds to CD20 on B-cells and to CD3 on T-cells, inducing activation and cytotoxic activity of T-cells and enabling lysis of CD20-expressing B-cells.1,4,7
Diagram of the T-cell receptor (TCR) complex.
- CD3 bispecific antibodies (bsAb) induce the activation and cytotoxic activity of effector T cells enabling lysis of target-expressing B-cells.1,3,7
- CD3 bsAb activate T cells by binding CD3 on T cells and a tumor-associated antigen (TAA), such as CD20, on the B-cells. Consequently, available T cells can bind to target-expressing cells irrespective of the peptide/major histocompatibility complex (MHC) specificity of their TCR.1,3
- Activation of the TCR-CD3 complexes leads to the formation of a cytolytic synapse between the T cell and the B-cell which results in the release of perforin and granzymes and subsequent B-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 the need for a format that either significantly limits or eliminates cyokine release syndrome (CRS) because CRS appears to be dose-limiting in most cases for this class of molecules.1
IMPLICATIONS IN CANCER
Immunotherapy of cancer with CD3 bsAb is a fast-developing field. Multiple TAAs are under evaluation for both hematological and solid tumor malignancies, with many different CD3 bsAbs in clincial development.3,7 The idea of using the cytotoxic capacity of T cells through CD3 bsAb to kill tumor cells dates back to the 1980’s.3,8
The CD20 receptor is a well-established target expressed by multiple B cell malignancies. Resistance is rarely caused by the loss of CD20 expression as evidenced by the presence of CD20 on B cells in the vast majority of patients previously treated with CD20-containing regimens.6
Bispecific antibodies that bind to both CD3 and CD20 can recruit T cells from the body’s own immune system to act as cytotoxic effectors against tumor cells.6
Related Research
- Strohl WR, Naso M. Bispecific T-cell redirection versus chimeric antigen receptor (CAR)-T cells as approaches to kill cancer cells. Antibodies (Basel). 2019;8(3):41.
- Alcover A, et al. Cell viology 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.
- Ratcliffe MJ, et al. Encyclopedia of Immunobiology. 2016.
- Hutchings M, et al. 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 ;52:102625.
- Labrijn AF, Janmaat ML, Reichert JM, Parren PWHI. Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 2019 ;18(8):585-608.
- Staerz UD, Kanagawa O, Bevan MJ. Hybrid antibodies can target sites for attack by T cells. Nature. 1985 ;314(6012):628-31.
