Abstract
Therapeutic monoclonal antibodies have become molecules of choice to treat autoimmune disorders, inflammatory diseases, and cancer. Moreover, bispecific/multispecific antibodies that target more than one antigen or epitope on a target cell or recruit effector cells (T cell, natural killer cell, or macrophage cell) toward target cells have shown great potential to maximize the benefits of antibody therapy. In the past decade, many novel concepts to generate bispecific and multispecific antibodies have evolved successfully into a range of formats from full bispecific immunoglobulin gammas to antibody fragments. Impressively, antibody fragments such as bispecific T-cell engager, bispecific killer cell engager, trispecific killer cell engager, tandem diabody, and dual-affinity-retargeting are showing exciting results in terms of recruiting and activating self-immune effector cells to target and lyse tumor cells. Promisingly, crystallizable fragment (Fc) antigen-binding fragment and monomeric antibody or half antibody may be particularly advantageous to target solid tumors owing to their small size and thus good tissue penetration potential while, on the other hand, keeping Fc-related effector functions such as antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cell-mediated phagocytosis, and extended serum half-life via interaction with neonatal Fc receptor. This review, therefore, focuses on the progress of Fc engineering in generating bispecific molecules and on the use of small antibody fragment as scaffolds for therapeutic development.
Highlights
Since approval of the first therapeutic monoclonal antibody muromonab-CD3 by the United States Food and Drug Administration for treatment of organ transplant-associated acute rejections in 1992, a total of 62 mAbs have been approved by the USFDA for clinical use as of May 2016 [1, 2]
We describe recent advances in the therapeutic potential of bispecific molecules and small Ab fragments as novel scaffolds
The light chains in the single-chain Fab (scFab) format were attached to the N-terminus of the heavy chain through a 32-residue linker, and heterodimer formation was achieved by KiH mutations
Summary
Since approval of the first therapeutic monoclonal antibody (mAb) muromonab-CD3 by the United States Food and Drug Administration for treatment of organ transplant-associated acute rejections in 1992, a total of 62 mAbs have been approved by the USFDA for clinical use as of May 2016 [1, 2]. BsAbs were generated by a quadroma technology, which required the somatic fusion of two hybridomas harboring different specificities [21, 22] This led to the foundation of bispecific antibody production for simultaneous targeting of two different antigens or epitopes on a cell (Figure 1A). Some bispecific antibodies and antibody fragments currently under clinical evaluation are listed (see Table 2), and graphical models of bispecific molecules under development are presented (see Figure 1)
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