Bispecific Antibody: A Dark Horse Heading Treatment Development for Multiple Diseases

Bispecific antibodies (bsAb) are antibody molecules constructed by genetic recombination, chemistry coupling or quadroma, containing two target-binding units, each of which independently recognizes a specific epitope. The concept of bsAb was first proposed in 1964, and it was not until 2014 that the first product, Blincyto, was approved. This is an anti-CD19/anti-CD3 bsAb, which was approved by the FDA for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia. Since then, bsAb has been extensively explored in clinical studies. To date, research on bsAb has broadened to include multiple types of disease.

New Findings on bsAb for TNBC

In the past 10 years, the amount of research devoted to bsAbs has increased significantly. The majority of oncology-related bsAbs in clinical development engage immune cells to destroy tumor cells, and bsAbs can also be used to block tumor signaling pathways or deliver cytotoxic payloads to tumors. In recent years, genetic engineering has increasingly been used to produce a variety of antibodies for greater flexibility in size, valence, specificity, half-life, and biodistribution.

On Oct 1, 2021, a new research was published on Journal for ImmunoTherapy of Cancer to introduce a bsAb, F7AK3, targeting triple negative breast cancer (TNBC). This antibody recognizes both trophoblast cell surface antigen 2 (TROP2) and CD3. In vivo antitumor activity of F7AK3 was investigated in a xenograft TNBC tumor model, using immunodeficient mice that were reconstituted with human peripheral blood mononuclear cells. The data demonstrate that F7AK3 has the potential to treat TNBC patients, which warrants further preclinical and clinical evaluation of the F7AK3 in advanced or metastatic TNBC patients.

New Findings on bsAb for HIV

Novel studies suggest that bsAbs could be a promising strategy for the in vivo elimination of HIV. HIV specific bsAb can perform being similar to cancer bsAb-based immunotherapies, which could target Env and simultaneously engage CD3 on CTLs (cytotoxic T lymphocytes). Recent work also proved that many bsAbs can induce a CTL-mediated killing of resting HIV-infected CD4+ T cells in vitro and reduce HIV protein expression ex-vivo. In the BiTE (bispecific T cell engager) format, the combination of domain 1 and 2 with a neutralizing scFv against gp120 and an anti-CD3 scFv demonstrated potent activity in targeting latently HIV-infected cells.

Understanding local, tissue effector immune cell populations and the molecular signature of HIV-infected cells is a hot topic of research right now. These findings might help researchers develop new bsAbs with more specificity and effectiveness, as well as identify molecular targets for bsAb-based HIV combination immunotherapies.

New Findings on bsAb for SARS-CoV-2

The team headed by Daniel Ruzek or Luca Varani from the University of Bellinzona and the Czech Academy of Sciences targeted two binding sites within the receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) protein to prevent generation of viral survivors. The engineered bispecific, IgG1-like molecule (CoV-X2) based on two antibodies derived from COVID-19 convalescent donors, C121 and C135, in vitro prevented detectable S binding to Angiotensin-Converting Enzyme 2 (ACE2), the virus cellular receptor.

Furthermore, CoV-X2 neutralized SARS-CoV-2 and its variants of concern, as well as the escape mutants generated by parental monoclonals. In a novel animal model of SARS-CoV-2 infection with lung inflammation, CoV-X2 protected mice from disease suppressing the generation of viral escape variants. Thus, simultaneous targeting of non-overlapping RBD epitopes by IgG-like bispecific antibodies is feasible and effective, combining into a single molecule the advantages of antibody cocktails. Dr. Luca Varani has talked in a free bsAb webinar held by Creative Biolabs to introduce the details of his research (the webinar recording is available on Creative Biolabs’ official website).



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