Bispecific Antibodies

Overview

We are exploring the potential of dual-targeted single agents. Bispecific antibodies (bsAbs) are engineered to recognize two different antigens or epitopes at the same time.1 These are also referred to as dual-specificity antibodies.1

diagram

Therapeutic Potential

The versatility of bispecific antibodies introduces a wide range of potential applications.1

  • bsAbs can be designed for multiple targeted approaches1:
    • Two epitopes on a single cancer target
    • 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

Novel Formats

Dual-Variable-Domain Immunoglobulins (DVD-IgTM)

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 penetration1

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; bispecific T cell engagers (BiTEs®) are based on this format.1
  • Dual-affinity retargeting molecules (DARTs): VH of the first variable region is linked to the VL on a second chain, and the VH of the second variable region is linked to the VL on the first chain; an inter-chain disulfide bond stabilizes the DART.1
  1. 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.
  2. 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.
  3. Sedykh SE, Prinz VV, Buneva VN, Nevinsky GA. Bispecific antibodies: design, therapy, perspectives. Drug Des Devel Ther. 2018;12:195-208.

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