The production of bispecific antibodies involves the addition of a second antigen-binding site in the Fab arms. Sometimes, these types of bispecific products have problems such as poor stability, immunogenicity and challenges in the manufacturing process. Hence, Mab2 simply replaces the Fc region of an existing antibody with an Fcab that binds to a second target of interest to create a full-length bispecific monoclonal antibody (Fig. 1a). It binds with the two different antigens at the same time with favorable pharmacokinetics, antibody-dependent cellular cytotoxicity, and excellent stability and ease of manufacturing.
Formats of bispecific antibodies (BsAbs)
Many formats have been developed for BsAb generation as listed in the following table.
Format | Schematic structure | Description | Example BsAb | Trademark | Company |
---|---|---|---|---|---|
tandem VHH | Tandem VHH fragment-based BsAb | N/A | |||
tandem scFv | Tandem ScFv fragment-based BsAb | AMG330 | BiTETM | Amgen | |
Dual-affinity re-targeting antibody | Tandem domain-exchanged Fv (can also be used to fuse with Fc domain to create whole Abs) | Flotetuzumab | DARTTM | Macrogenics | |
Diabody | dimer of single-chain Fv (scFv) fragment | vixtimotamab | ReSTORETM | Amphivena Therapeutics | |
(scFv)2-Fab | a Fab domain and two scFv domains bind | A-337 | ITabTM | Generon/EVIVE Biotech | |
Rat–mouse hybrid IgG | Full-size IgG-like half antibodies from two different species | Catumaxomab | TriomabTM | Trion Pharma | |
Hetero heavy chain, Common light chain | Hetero heavy chain, Common light chain | Emicizumab | ART-IgTM | Genentech/ Chugai/Roche | |
Controlled Fab arm exchange | Recombin the parental half antibodies | JNJ-64007957 | DuobodyTM | Genmab/ Janssen | |
Hetero H, forced HL IgG1 | KIH technology for heterodimerization of 2 distinct H chains, replacing the native disulfide bond in one of the CH1-CL interfaces with an engineered disulfide bond to enhance the cognate of H and L paring | MEDI5752 | DuetMabTM | MedImmune/ AstraZeneca | |
cH IgG1 | Identical heavy chains; 2 different light chains: one kappa (κ) and one lambda (λ) | NI-1701 | κλ bodyTM | Novimmune SA | |
Hetero H, CrossMab | KIH technology; domain crossover of immunoglobulin domains in the Fab region | Vanucizumab | CrossMabTM | Roche | |
scFv-Fab IgG | Fab-Fc; ScFv-Fc | Vibecotamab; M802 | XmabTM (the engineered Fc to enhance the generation of heterodimeric Fc); YBODYTM | Xencor/Amgen; YZYBio | |
VH1-VH2-CH1-Fc1(G1) x VL2-VL1-CL-Fc2(G1) | 2 binding motif in one half antibody | SAR440234 | CODV-IgTM | Sanofi | |
VL1-CL1-VH2-CH2-Fc x VH1-CH1 x VL2-CL2 | 2 binding motif in one half antibody | EMB-01 | FIT-IgTM | EPIMAB BIOTHERAPEUTICS | |
VH-1-TCR Cα x VL-1-TCR Cβ; VH-2-CH-2-Fc x VL-2-CL-2 | KIH technology; TCR Cα/Cβ is used to substitute the CH1 and CL domain in one arm | WuXibodyTM | WuXi Biologics | ||
C-terminal linker of Fc | Link the other molecules at the C-terminal of Fc | APVO442 | ADAPTIR-FLEXTM | Aptevo Therapeutics | |
Fc antigen binding site | 2 natural binding sites; 2 additional binding sites in the Fc loop | FS118 | mAb2 | F-star Therapeutics |