Pipeline and MOA (mechanism of action) of bispecific antibodies (BsAbs)

Bridge of 2 cells (engagers)

By binding with 2 antigens from 2 different cells, the BsAbs can physically link them together, thus these kinds of BsAbs are named “engagers”. The redirecting of immune cells to tumor cells by the engagers makes the immune cell activated and then eliminate the target cells. The T cell engagers are the most popular BsAbs which account for nearly half of the clinical trials aimed evaluating the BsAbs. NK cell engagers are recently developed BsAbs for NK cell-dependent tumor cell elimination.

The engagers in research, clinical trials and market are listed below. Genemedi offers the high quality, premade benchmark BsAbs for researchers.

Targeting multiple receptors

Bridging receptors is an obligate mechanism in which the binding of BsAbs to 2 receptors causes the activation or inhibition of each receptor. The co-activation or inhibition synergistically enhanced the biological effect of single antibody.

ligand redundancy

In addition to bind to the receptors, targeting redundancy for cytokines or angiogenesis factors represents an area of interest for BsAbs.

Biparatopic bsAbs

Instead of targeting two different proteins, bsAbs may be designed to simultaneously bind to two non-overlapping epitopes on the same target. Biparatopic targeting builds on increasing binding strength through antigen crosslinking and aggregation, thereby mimicking effects observed for antibody mixtures and polyclonal antibodies. Biparatopic bsAbs are therefore essentially a combinatorial concept

Cofactor mimetics

BsAbs can also be designed as a scaffold or cofactor linking enzyme and substrate together. One of the applications is the BsAbs used as a substitution of a critical clotting factor in the treatment of hemophilia.

Piggyback approaches

Exploit the first binding specificity of a BsAb as a transport modality for the second specificity are named the “piggyback” approaches. To cross the blood-brain barrier, one binding arm of the BsAbs are designed to target the transferrin receptor (TfR). The human serum albumin (HSA) targeting domain are used to extent the half-life of BsAbs, especially to BsAbs without Fc, for example the tandem ScFvs or VHHs. In addition, the piggyback approaches are also been used in promoting the degradation of pathogens.

Introduction about bispecific antibodies (BsAbs)

Bispecific antibodies (BsAbs) are designed to bind two different epitopes or antigens, which leads to multiple mechanistic functions with synergistic effects. The attractive feature is their potential for novel functionalities, which do not exist in mixtures of the parental or reference antibodies. Till now, more than 200 BsAb-based clinical trails have been registered on and 4 BsAbs (with one withdraw) have been granted FDA approval. The promising future makes BsAbs attracting more attentions.

The connecting of two specificities within one BsAb can be exploited for novel therapeutic concepts. The mostly applications of BsAbs are recruiting effector cells to the target cells, which are regarded as the immune cell engagers. The redirection of the cytotoxic effector cells (T and NK cells) to the targeting cancer cells by BsAbs physically link them together and activate the effector cells to eliminate the target ones. In addition, the BsAbs can also be used to link two molecules together to make the therapeutic effects such as the dual inhibition of immune checkpoints, the conditionally activate a growth factor receptor for diabetes treatment and the replacement of natural bridge molecules such as the coagulation factor VIII. More innovative designs of BsAbs can be achieved in the future.

To accelerate the development of BsAbs, Genemedi offers the high quality, premade benchmark BsAbs for researchers. The biosimilars are expressed by mammalian cell line and used for biological drug discovery items including cell culture, assay development, animal model development, PK/PD model development (Pharmacokinetics & Pharmacodynamic) and mechanism of action (MOA) research.

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 Picture loading failed. Tandem ScFv fragment-based BsAb AMG330 BiTETM Amgen
Dual-affinity re-targeting antibody Picture loading failed. Tandem domain-exchanged Fv (can also be used to fuse with Fc domain to create whole Abs) Flotetuzumab DARTTM Macrogenics
Diabody Picture loading failed. dimer of single-chain Fv (scFv) fragment vixtimotamab ReSTORETM Amphivena Therapeutics
(scFv)2-Fab Picture loading failed. a Fab domain and two scFv domains bind A-337 ITabTM Generon/EVIVE Biotech
Rat–mouse hybrid IgG Picture loading failed. Full-size IgG-like half antibodies from two different species Catumaxomab TriomabTM Trion Pharma
Hetero heavy chain, Common light chain Picture loading failed. Hetero heavy chain, Common light chain Emicizumab ART-IgTM Genentech/ Chugai/Roche
Controlled Fab arm exchange Picture loading failed. Recombin the parental half antibodies JNJ-64007957 DuobodyTM Genmab/ Janssen
Hetero H, forced HL IgG1 Picture loading failed. 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 Picture loading failed. Identical heavy chains; 2 different light chains: one kappa (κ) and one lambda (λ) NI-1701 κλ bodyTM Novimmune SA
Hetero H, CrossMab Picture loading failed. KIH technology; domain crossover of immunoglobulin domains in the Fab region Vanucizumab CrossMabTM Roche
scFv-Fab IgG Picture loading failed. Fab-Fc; ScFv-Fc Vibecotamab;
XmabTM (the engineered Fc to enhance the generation of heterodimeric Fc);
Xencor/Amgen; YZYBio
VH1-VH2-CH1-Fc1(G1) x VL2-VL1-CL-Fc2(G1) Picture loading failed. 2 binding motif in one half antibody SAR440234 CODV-IgTM Sanofi
VL1-CL1-VH2-CH2-Fc x VH1-CH1 x VL2-CL2 Picture loading failed. 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 Picture loading failed. 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 Picture loading failed. Link the other molecules at the C-terminal of Fc APVO442 ADAPTIR-FLEXTM Aptevo Therapeutics
Fc antigen binding site Picture loading failed. 2 natural binding sites; 2 additional binding sites in the Fc loop FS118 mAb2 F-star Therapeutics

Bispecific Antibody Development Programs Guidance for Industry by FDA

FDA set up the guidance for the development of BsAbs. The link and PDF files are listed below.

Bispecific Antibody Development Programs Guidance for Industry

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Source: Genemedi    2019-02-26

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