Fig. 3

Various formats and categories of bsAbs. a Examples of common bsAb formats. Short bars indicate the antibody Fab segment, long bars indicate the Fc segment, and for ImmTAC, the Fab segment is linked to an antigen-specific TCR. In the same antibody icon, different color combinations of the Fab segment indicate the binding to different target proteins. BsAb examples of these formats are in the gray box. b According to our statistics of bsAbs that have entered clinical trials, the TCEs comprising the anti-CD3 scFv account for about half of all bsAbs under development at present. The development of other bsAb categories presents a diversified landscape. The two ends of each arc indicate two targets of bsAbs. Only bsAbs are counted for this figure, with msAbs with higher valency excluded. The data of this figure are consistent with Table 2 and Supplementary Table 4. The statistic is up to October 2022 and bsAbs with terminated development are excluded. c Prism of developmental strategies of bsAbs. The strategy of bsAb development is mainly to combine four types of targets: immune cell targets, tumor cell targets, co-stimulatory molecules/immunostimulatory cytokines, and immune checkpoints or other immunosuppressive molecules. By these designs, immune cells and immunomodulatory signals can be introduced into the TAA-expressing environment. The black lines on the edge of the prism indicate that the corresponding bsAb category targets the target types directed by the arrows: (1) TCEs and NKEs; group I general bsAbs: (2) co-stimulatory molecule × TAA or TME protein and (3) co-stimulatory molecule × co-stimulatory molecule; group II general bsAbs: (4) inhibitory checkpoint × TAA and (5) inhibitory checkpoint × inhibitory checkpoint; group III general bsAbs: (6) inhibitory checkpoint × co-stimulatory molecule. d Mechanism-of-action of bispecific cell engagers and group I-III general immunoregulatory anti-cancer bsAbs. DART dual-affinity retargeting, scFv single-chain variable fragment, TAA tumor-associated antigen, HLA human leukocyte antigen, HSA human serum albumin, TriTAC Tri-specific T cell activating construct, CAF cancer-associated fibroblast, FAP fibroblast activation protein