Inspiring Immuno-oncology Therapeutics Based on Novel Bispecific Fusion Proteins

The discovery of treating cancer by activating the immune system was honored with a Nobel Prize as early as 2018, and the development of immuno-oncology agents has moved further in recent years. However, these single agents are not satisfying enough for many patients in many conditions, which impels researchers to turn attention to combination therapeutics, i.e. using two or more agents together to treat cancer.

One of the most representative and influential immuno-oncology agents is the novel generation of bispecific fusion proteins. Due to the ability to simultaneously attach to two different antigens, bispecific antibodies (BsAb) are equipped with complex biological activities and can recognize a tumor antigen and a receptor on T cells to avoid antigenic escape.

Inspired by the inspiring outlook on the global bispecific antibody therapeutics market, an increasing number of companies have stepped into this space in recent years. Creative Biolabs, in contrast, is a life science company dedicated to BsAb development for years and has become a leader in this branch of bispecific antibody analysis and generation.

Problems in Immuno-oncology Therapeutics Application

Though small recombinant BsAb formats perform well in retargeting T cells to tumor cells in vitro and in vivo, studies promptly shed light on some problems in the practical process of therapeutic applications. These small BsAb molecules have molecular masses between 50 and 60 kDa, which makes them easy to be cleared from circulation in a short time with an incipient half-life of less than 30 min, which may require high-dose and constant injections or infusions.

To address this issue, bispecific fusion proteins are generated with more functionality or specificity. The principle of bispecific fusion protein generation is to bind the antibody or antibody fragments to other proteins, such as specific receptors of lymph cells, another Fab molecule, and a specific ligand of the tumor cell receptor.

Bispecific antibody-HSA Fusion Proteins

Scientists embark on promoting the pharmacokinetic properties of small molecules by fusing BsAb with human serum albumin (HSA), thus improving the apparent molecular size of the recombinant protein. Albumin is a 67 kDa monomeric protein generated in the liver, taking the most abundant protein part in the blood plasma. The BsAb-HSA fusion proteins typically have a higher affinity, stronger stability, and an improved serum half-life in mice compared with parental antibodies, and are widely applied in therapy and diagnostic research.

BsAb-toxin Fusion Proteins

In addition to bispecific antibody-HSA fusion proteins, another novel fusion protein is the BsAb-toxin fusion protein. Taking advantage of the cancer-specific targets and tumor-reactive ligands, targeted toxins (TTs) could be a set of selective therapeutic molecules against a number of human cancer types. The designed purpose of specifically break cancerous cells without damaging healthy cells has endowed TTs with great potential in therapies.

Tandem scFv-toxin, also known as the bispecific ligand-directed toxin (BLT), is one of the most representative and most widely used BsAb-toxin fusion proteins for its better activities and increased total targeting capability, and now can be an alternative therapy in anti-tumor treatment.

Up to now, a wide range of preclinical and clinical trials have been undergoing to develop possible immuno-oncology therapeutics, including lung cancer, human HPV-associated cancers, biliary tract cancer, gastric cancer, non-Hodgkin's lymphoma, and acute lymphoblastic leukemia. All in all, the generation and engineering of bispecific fusion proteins allow more treatment potentials for tumors.