Overview of Bispecific Fusion Proteins

Bispecific fusion proteins (BFPs) are a class of biopharmaceuticals that combine two or more functional domains from different molecules, such as antibodies, receptors, ligands, enzymes, or toxins, to simultaneously target multiple antigens or pathways. BFPs have several advantages over conventional monoclonal antibodies (mAbs), such as higher specificity, lower dosage, broader applicability, and multiple mechanisms of action. However, BFPs also face some challenges, such as complex bioanalysis, immunogenicity, toxicity, and stability. BFPs have shown promising potential in various therapeutic areas, such as oncology, ophthalmology, and autoimmune diseases, and some of them have entered clinical trials or even been approved for marketing.

Overview of ImmTAC

ImmTAC is a technology that uses engineered T-cell receptors (TCRs) to target cancer cells and activate T cells. ImmTAC stands for immune-mobilizing monoclonal TCRs against cancer. It is a type of bispecific fusion protein that consists of two parts: a monoclonal TCR (mTCR) and an anti-CD3 single-chain variable fragment (scFv). The mTCR is a genetically engineered TCR that can bind to a specific peptide-MHC complex on the surface of cancer cells. The anti-CD3 scFv is a fragment of an antibody that can bind to CD3, a molecule on the surface of T cells. By linking these two parts together, ImmTAC can simultaneously bind to both cancer cells and T cells, forming a bridge that brings them into close proximity. This triggers the activation and proliferation of T cells, which then kill the cancer cells. The ImmTAC technology can achieve high specificity by using mTCRs that recognize unique peptide-MHC complexes that are specific to cancer cells. The ImmTAC technology can also target a wide range of antigens that are not accessible by antibodies, such as intracellular proteins, mutated proteins, or viral proteins. Moreover, the ImmTAC technology can induce multiple mechanisms of action, such as direct cytotoxicity, cytokine release, immune memory, and immune modulation. However, the ImmTAC technology may cause side effects such as cytokine release syndrome, neurotoxicity, or off-target toxicity, due to the potent activation of T cells and the potential cross-reactivity of mTCRs. The ImmTAC technology may also encounter resistance from cancer cells, such as downregulation of MHC molecules, loss of antigen expression, or immune evasion. Furthermore, the ImmTAC technology has some limitations, such as the requirement of MHC restriction, the difficulty of identifying suitable antigens, and the complexity of manufacturing and delivery.

Overview of HSAbody

HSAbody is a technology that uses human serum albumin (HSA) as a binding domain to enhance the pharmacokinetics and stability of bispecific fusion proteins (BFPs). HSA is the most abundant protein in human blood plasma, with a half-life of about 19 days. By fusing HSA to BFPs, the HSAbody technology can extend the circulation time and reduce the clearance of BFPs, as well as improve their solubility and stability. The HSAbody technology can achieve long-lasting pharmacokinetics by using HSA as a binding domain, which can bind to the endogenous HSA in the blood and extend the half-life and reduce the clearance of BFPs. The HSAbody technology can also enable low-dose administration of BFPs, as the HSA domain can increase the affinity and avidity of BFPs for their targets, resulting in a potent effect. Moreover, the HSAbody technology can reduce the immunogenicity of BFPs, as the HSA domain is derived from human protein and is less likely to elicit an immune response than foreign protein domains. However, the HSAbody technology may cause cross-reactivity in BFPs, as the HSA domain may bind to non-target proteins that share some similarity with HSA, causing unwanted side effects. The HSAbody technology may also induce toxicity in BFPs, as the HSA domain may alter the biodistribution and accumulation of BFPs in certain organs or tissues, leading to adverse effects. Furthermore, the HSAbody technology has some limitations, such as the requirement of HSA availability, the difficulty of identifying suitable targets, and the complexity of manufacturing and delivery.

Overview of scDiabody-HAS

scDiabody-HAS is a type of bispecific fusion protein that combines two single-chain diabodies (scDiabodies) with a human serum albumin (HSA) binding domain. scDiabodies are composed of two single-chain Fv (scFv) fragments connected by a short linker peptide, forming a cross-over dimer with two antigen binding sites. The HSA binding domain is derived from a bacterial protein called streptococcal protein G, which has a high affinity and specificity for HSA. By fusing the HSA binding domain to the scDiabodies, the scDiabody-HAS fusion protein can bind to the abundant HSA in the blood, enhancing its affinity and stability. The advantages of the scDiabody-HAS technology include simple expression, high targeting, and a long half-life. The scDiabody-HAS fusion protein can be expressed in bacterial or mammalian cells and purified by affinity chromatography. The scDiabody-HAS fusion protein can bind to two different antigens with high affinity and specificity, resulting in a synergistic effect. The scDiabody-HAS fusion protein can also bind to HSA in the blood, extending its half-life and reducing its clearance. The challenges of the scDiabody-HAS technology include possible immunogenicity and cross-reactivity. The scDiabody-HAS fusion protein may elicit an immune response against the foreign protein domains, such as the HSA binding domain or the linker peptide. The scDiabody-HAS fusion protein may also bind to non-target antigens that share some similarity with the target antigens, causing unwanted side effects.

Overview of Tandem scFv-Toxin

Tandem scFv-Toxin is a type of bispecific antibody-toxin fusion protein that can target and kill specific cells, such as cancer cells. It is composed of two single-chain Fv (scFv) fragments, which are the smallest functional units of antibodies, and a truncated toxin, which is a modified version of a bacterial or plant toxin that can enter the cytosol and induce cell death. The two scFv fragments are linked together by a flexible peptide linker, and the toxin is fused to the C-terminus of the second scFv. The two scFv fragments can bind to different antigens on the same cell surface, such as CD19 and CD22 in B cell malignancies, and deliver the toxin to the target cell. The toxin then enters the cell through endocytosis and disrupts protein synthesis, leading to apoptosis. Tandem scFv-Toxin has several advantages over conventional bispecific antibodies, such as increased specificity, stability, and potency, as well as reduced immunogenicity and production cost. Tandem scFv-Toxin has been developed for various diseases, such as leukemia, lymphoma, ovarian cancer, and prostate cancer, and has shown promising results in preclinical and clinical studies.

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