Mechanism of Action and Pharmacokinetics of Approved Bispecific Antibodies

Abstract

Bispecific antibodies represent a significant advancement in therapeutic antibody engineering, offering the ability to simultaneously target two distinct antigens. This dual-targeting capability enhances therapeutic efficacy, especially in complex diseases, such as cancer and autoimmune disorders, where drug resistance and incomplete target coverage are prevalent challenges. Bispecific antibodies facilitate immune cell engagement and disrupt multiple signaling pathways, providing a more comprehensive treatment approach than traditional monoclonal antibodies. However, the intricate structure of bispecific antibodies introduces unique pharmacokinetic challenges, including issues related to their absorption, distribution, metabolism, and excretion, which can significantly affect their efficacy and safety. This review provides an in-depth analysis of the structural design, mechanisms of action, and pharmacokinetics of the currently approved bispecific antibodies. It also highlights the engineering innovations that have been implemented to overcome these challenges, such as Fc modifications and advanced dimerization techniques, which enhance the stability and half-life of bispecific antibodies. Significant progress has been made in bispecific antibody technology; however, further research is necessary to broaden their clinical applications, enhance their safety profiles, and optimize their incorporation into combination therapies. Continuous advancements in this field are expected to enable bispecific antibodies to provide more precise and effective therapeutic strategies for a range of complex diseases, ultimately improving patient outcomes and advancing precision medicine.

Keywords: Antibody engineering; Bispecific antibody; Dual-targeting therapy; Immunotherapy; Mechanism of action; Pharmacokinetics.

Fig. 1

Structure of approved bispecific antibodies. (A) Bispecific antibodies with IgG-like structures. The figure presents the approved BsAbs with IgG-like structures. These structures consist of two heavy chains (with constant regions depicted in light blue and VH domains highlighted in various colors) and two light chains (with constant domains also shown in light blue and VL domains in different colors). (B) Non-IgG-like bispecific antibodies. The figure is organized according to the approval date. ANG-2, angiopoietin-2; BCMA, B cell maturation antigen; cMET, c-mesenchymal-epithelial transition factor; CTLA4, cytotoxic T lymphocyte-associated antigen 4; EGFR, epidermal growth factor receptor; EpCAM, epithelial cell adhesion molecule; FX, coagulation factor X; FIXa, coagulation factor IXa; GPRC5D, G-protein-coupled receptor class C group 5 member D; gp100, glycoprotein 100; PD1, programmed cell death protein 1; scFv, a single-chain variable fragment; TCR, T-cell receptor; VEGF, vascular endothelial growth factor; 6HIS, 6X his-tag.

Fig. 2

Modes of action of approved bispecific antibodies. (A) Effector cell engagement through CD3 on T cells. CD20 (mosunetuzumab, epcoritamab, glofitamab), BCMA (teclistamab, elranatamab), CD19 (blinatumomab), and GPRC5D (talquetamab) on hematological tumors; gp100 (tebentafusp) and EpCAM (catumaxomab) on solid tumors. (B) Checkpoint binding-mediated immune cell co-stimulation; PD-1/CTLA-4 (cadonilimab). (C) Cell signal inhibition by the blockade of two signaling receptors; EGFR/MET (amivantamab). (D) Cell signal inhibition by the neutralization of soluble two ligands; VEGF-A/ANG-2 (faricimab). (E) Coagulation factor replacers. Factor X/Factor IXa (emicizumab). ANG-2, angiopoietin-2; BCMA, B cell maturation antigen; cMET, c-mesenchymal-epithelial transition factor; CTLA4, cytotoxic T lymphocyte-associated antigen 4; EGFR, epidermal growth factor receptor; EpCAM, epithelial cell adhesion molecule; FX, coagulation factor X; FIXa, coagulation factor IXa; GPRC5D, G-protein-coupled receptor class C group 5 member D; gp100, glycoprotein 100; PD-1, programmed cell death protein 1; VEGF-A, vascular endothelial growth factor-A.