BI-SPECIFIC ANTIBODIES
OVERVIEW
Antibodies (Abs) containing two different antigen-binding sites in one molecule are called bispecific.2,3
There are numerous types of bispecific antibodies, including:2,3
- DVD-Ig (dual-variable-domain immunoglobulin): blockade of proinflammatory cytokines
- T cell-redirecting bispecific antibodies (TRBAs): retargeting of T cells to tumors
Examples of Bispecific Formats1
Dual-Variable-Domain Immunoglobulins (DVD-Ig)
A DVD-Ig combines the target-binding variable domains of two monoclonal antibodies, fused in tandem via naturally occurring or glycine-serine linkers to create a tetravalent, dual-targeting single agent.2,3
- Bispecific and bivalent with regard to each antigen3
- Able to simultaneously bind antigens with all variable domains3
- Potentially allows less frequent administration3
Formats based on single-chain variable fragments (scFv)
ScFv-based bsAbs are fusions of only the variable regions of the heavy (VH) and light chains (VL) of immunoglobulins, connected with a short linker peptide.1
- Exhibit high tumor specificity and tissue penetration.1
Examples include:
- Tandem scFvs: Two scFvs are connected in a tandem orientation by a flexible linker that permits the antigen-binding sites to rotate freely.1
Therapeutic Potential
The versatility of bispecific antibodies introduces a wide range of potential applications.1
bsAbs can be designed for multiple targeted approaches:1
- Two epitopes on a single cancer target1
- Two distinct antigens on the same tumor cell
- Two antigens on different cells within the tumor microenvironment
bsAbs can direct protein-protein interactions by targeting different proteins on the same cell.1
- This allows for more efficient modification of cell signaling, potentially resulting in the deactivation of proliferation or inflammatory pathways.
They can also direct cell action in a specific setting by addressing two targets on different cell types.1
- This allows for mediating the redirection of immune effector cells, such as NK cells and T cells, to tumor cells in order to potentially enhance tumor destruction.1
Relevant Targets
- Fan G, Wang Z, Hao M, Li J. Bispecific antibodies and their applications. J Hematol Oncol. 2015;8:130. doi: 10.1186/s13045-015-0227-0.
- Gu J, Ghayur T. Generation of dual-variable-domain immunoglobulin molecules for dual-specific targeting. In: Wittrup KD, Verdine GL, eds. Methods in Enzymology, Volume 502. Elsevier Science; 2012:25-41.
- Sedykh SE, Prinz VV, Buneva VN, Nevinsky GA. Bispecific antibodies: design, therapy, perspectives. Drug Des Devel Ther. 2018;12:195-208.
