Bispecific monoclonal antibody
A bispecific monoclonal antibody (BsMAb, BsAb) is an artificial protein that can simultaneously bind to two different types of antigen or two different epitopes on the same antigen.[1] Naturally occurring antibodies typically only target one antigen. BsAbs can be manufactured in several structural formats. BsAbs can be designed to recruit and activate immune cells, to interfere with receptor signaling and inactivate signaling ligands, and to force association of protein complexes.[2] BsAbs have been explored for cancer immunotherapy, drug delivery, and Alzheimer's disease.[1][3]
Development history[edit]
The original concept of BsAbs was proposed by Nisonoff and his collaborators in the 1960s, including the first idea of antibody architecture and other findings.[4][5] In 1975, the problem of producing pure antibodies was solved by the creation of hybridoma technology, and the new era of monoclonal antibodies (MoAbs) came.[6] In 1983, Milstein and Cuello created hybrid-hybridoma (quadroma) technology.[7] In 1988, the single-chain variable fragment (scFv) was invented by the Huston team to minimize the refolding problems, which contains the incorrect domain pairing or aggregation of two-chain species.[8] In 1996, the BsAbs became more developed when the knobs-into-holes technology emerged.[1][9]
Advantages over ordinary monoclonal antibodies[edit]
Cancer immunotherapy with ordinary monoclonal antibodies does not activate T-lymphocytes because the Fab regions are already used for binding the tumor cells, and this type of cell does not have Fc receptors.[26] Bispecific antibodies also have a higher cytotoxic potential, and bind to antigens that are expressed relatively weakly.[27] The effective dose is around 0.01 mg·m−2·d−1 (milligrams per square meter body surface area per day), which is several orders of magnitude lower than with ordinary antibodies.[26] For non-IgG-like BsAbs, their smaller size allows them to reach antigens usually unavailable to conventional antibodies.[3] In the case of Ebola vaccines, this method allows the antibody to target intracellular targets not usually accessible by traditional monoclonal antibody treatments.[23]
Additionally, targeting more than one molecule can be useful to circumvent the regulation of parallel pathways and avoid resistance to the treatment. Binding or blocking multiple targets in a pathway can be beneficial to stopping disease, as most conditions have complicated multifaceted effects throughout the body.[28] Together with combination therapies, BsAbs are being used more and more to treat certain types of cancers, as, over time, some tumors develop resistances to checkpoint inhibitors and/or co-stimulatory molecules.[29]
Current Scenario of bsAb drugs[edit]
Currently, nine bsAb drugs have been approved by the US FDA / EMA and over 180 are currently in clinical trials. The first bispecific antibody to gain regulatory approval, blinatumomab, targets CD19 on B cells and CD3 on T cells, leading to the activation of T cells and the destruction of B cells.[30] A total of eight more bispecific antibody drugs have since been approved by the US FDA: blinatumomab, emacizumab, amivantamab, tebentafusp, faricimab, teclistamab, mosunetuzumab, epcoritamab, glofitamab.[31] Among the bsAb programs currently under development, the combination of CD3 and tumor surface targets are the most popular targets pairs. Other popular targets are CD3, HER2, PD-1, PD-L1, EGFR, CTLA-4, etc., which as well as immune targets of PD-1, PD-L1, BCMA, CD47, CTLA-4, LAG-3, 4 -1BB.[32] Additionally, with the approval of the several new bsAb since 2022, and new mechanisms for improving efficacy like development of hetero-dimer bispecific molecules, several additional possibilities of target pairs have emerged.[32]
Problems and current disadvantages[edit]
IgG-like antibodies can be immunogenic, which means the Fc region could cause detrimental downstream immune responses caused by cells that are activated by Fc receptors.[3] The therapeutic use of BsAbs as a whole is still largely in development, with many clinical trials currently ongoing that are determining the efficacy and safety of BsAbs for treatment.[14]