Bispecific monoclonal antibody
[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.
[20] Even though non-IgG-like BsAbs have low molecular weight and thus high tumor tissue permeability, their half-life is relatively short and they require multiple doses.
[1] Despite the considerable differences between the various types and formats of bispecific antibodies, their manufacturing processes correspond in several steps: The binding of a BsAb to its target antigens can lead to a variety of effects.
Catumaxomab, one of the first trifunctional antibodies approved for therapeutic use, binds both CD3 on cytotoxic T cells and EpCAM on human adenocarcinomas.
To improve the therapeutic efficacy, simultaneously interfering/blocking of two (or more) RTK signaling pathways, achieved through the mediation of BsAb to inactivate either the RTKs or their ligand, reduces the possibility of the escape mechanisms adopted by the tumor cells.
[22][23] In addition, in working with Ebolavirus vaccines, a study has shown that a DVD-Ig antibody can be used to prevent viral escape from the endosome.
Researchers developed DVD-Igs where the outer variable regions bind to the surface glycoproteins of the viral coat and enter the cell with the virus.
[24] As an example, emicizumab (formerly RG6013) is an IgG derivative containing H-chain heterodimerization motifs, which was combined with the common light chain approach to prevent L-chain mispairing issues.
However, the humanized BsAb has lower immunogenicity and long serum half-life compared with FVIII and thus provide a better treatment for hemophilia.
[28] 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.
Binding or blocking multiple targets in a pathway can be beneficial to stopping disease, as most conditions have complicated multifaceted effects throughout the body.
[29] 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.
[31] Additional bispecific antibody drugs have since been approved by the US FDA: emicizumab, amivantamab, tebentafusp, faricimab, teclistamab, mosunetuzumab, epcoritamab, glofitamab.
[32] A primary issue accompanying BsAb development since the early stages has been achieving a high ratio of correctly paired bispecific antibodies.
Novel pairing technologies have been developed to increase the heterodimerization rate, leading to higher yields and reduced production costs.
[15] One major area of concern is the feasibility of administration and management of side effects, where the potential for therapeutic success must be weighed against possible risks.
These factors have to be individually examined for each patient in order to evaluate the feasibility of a bispecific antibody treatment, and to assess the risk of infusion-related, immune-related, organ-specific, and hematologic side effects.
[35] Amivantamab, which targets epidermal growth factor (EGF) and MET receptors, for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations.
