Bispecific antibodies for viral immunotherapy

Abstract

Bispecific antibody engineering, in which binding specificities toward 2 distinct epitopes are combined into a single molecule, can greatly enhance immunotherapeutic properties of monoclonal antibodies. While the bispecific antibody approach has been applied widely to targets for indications such as cancer and inflammation, the development of such agents for viral immunotherapy is only now emerging. Here, we review recent advances in the development of bispecific antibodies for viral immunotherapy, highlighting promising in vitro and in vivo results.

Design and evaluation of bi- and trispecific antibodies targeting multiple filovirus glycoproteins

“…A good example of this latter principle is the development of "Trojan horse" bsAbs that engage the ebolavirus GP RBS deep within the endosomal pathway (18). The results with bsAbs and tsAbs presented here, and in other reports for filoviruses and other viral pathogens (25,26), indicate that multispecific antibodies may exhibit enhanced properties relative to canonical monospecific mAbs that are particularly beneficial for immunotherapy.…”

“…Multispecific mAbs have been utilized extensively in oncology, but their applications in viral immunotherapy are only now emerging (25). At present, the true immunotherapeutic potential of multispecific, engineered mAbs in relation to combinations of traditional mAbs remains to be determined.…”

“…We and others have been exploring multispecific antibody engineering strategies as a complementary approach to generation of cross-protective antibodies (25,26). We showed recently that combining two species-specific variable domains into a bispecific antibody (bsAb) confers cross-protection in mice for EBOV and SUDV (27).…”

Multispecific, Multivalent Antibody‐Based Molecules Engineered on the DART® and TRIDENTTM Platforms

“…Bispecific antibodies have also been developed for tumor targeting by other effector cells (NK cells, macrophages, neutrophils) by binding to activating Fc receptors on these cells (Duval, Posner, & Cavacini, 2008; Gleason et al., 2014; Johnson et al., 2010; Rothe et al., 2015). The concept of retargeting cytotoxic T cells to cells expressing specific cell‐surface proteins can be extended to virus‐infected cells (Nyakatura, Soare, & Lai, 2017). DART molecules binding to human immunodeficiency virus (HIV) envelope proteins and CD3 were able to redirect ex vivo polyclonal CD8+ T cells from both HIV‐seronegative and HIV‐seropositive donors to kill HIV‐infected CD4+ T cells (Sloan et al., 2015; Sung et al., 2015).…”

Fab-Arm Exchange Combined with Selective Protein A Purification Results in a Platform for Rapid Preparation of Monovalent Bispecific Antibodies Directly from Culture Media

“…For the treatment of cancer, bsAbs have a potential advantage over mAbs due to their exquisite specificity, which may allow for the specific targeting of discrete tumor populations as well as simultaneous modulation of multiple signaling pathways necessary for aberrant cell growth and survival [11]. Furthermore, the genetic diversity of many pathogenic viruses has significantly limited the therapeutic efficacy of mAbs, which can potentially be overcome by targeting multiple distinct epitopes with bsAbs [12][13][14]. Finally, bsAbs, have shown great potential for immune-modulation through the recruitment of effector cells to clear aberrant cells [9,11].…”