While a typical antibody molecule has two identical antigen-binding sites, bispecific antibodies (bsAbs) recognise two different epitopes. This makes them suitable for applications which include the recruitment of T cells to tumours, simultaneous blocking of two different signalling pathways, and the delivery of therapeutic agents to targeted sites.
The most well-known bsAbs are epitomised by catumaxomab (Removab®) and blinatumomab (Blincyto®), both of which have been approved for therapeutic use within the last decade. Catumaxomab, the first bsAb to be approved for cancer treatment, is a monoclonal bispecific trifunctional antibody (TrAb) which binds T cells via CD3, and tumour cells via the epithelial cell adhesion molecule (EpCAM). The Fc region provides a third functional binding site which recruits various accessory cells, resulting in a complex immune response that eliminates the tumour cells. Catumaxomab has been used successfully as an intraperitoneal treatment for patients with malignant ascites, a condition which occurs in individuals with metastasising cancers.
Blinatumomab represents a different type of bsAb, known as a bispecific T cell engager antibody (BiTE®). It comprises two antigen binding domains joined by a non-immunogenic linker and attaches CD3-positive T cells to CD19, a pan B cell marker, leading to T cell-mediated lysis of the B cells. Since CD19 is expressed on the majority of B cell malignancies it is a highly attractive target for antibody-based therapies. Currently the main application of blinatumomab is the treatment of relapsed/refractory B-cell precursor acute lymphoblastic leukaemia (BCP-ALL).
In recent years, antibodies have become a preferred option to chemotherapy and radiotherapy for cancer treatment since they are highly specific and afford a low toxic profile. Yet cancer cells continue to devise new ways of evading immunotherapy. Bispecific antibodies show promise as the next generation of antibody-based cancer therapeutics since they offer several potential advantages over monoclonal antibody approaches.
By redirecting specific immune cells to tumour cells to enhance tumour killing, bsAbs may enable treatment programmes to be shortened, which could decrease the likelihood of a patient developing drug resistance. Blocking multiple signalling pathways may slow or prevent pathogenesis, for example by preventing cross-talk between different tumour cell receptors to reduce proliferation or limit angiogenesis. Delivery of payloads such as drugs or radiolabels to tumours is another attractive treatment strategy afforded by bsAbs.
Bispecific antibodies are complex molecules, and their development and manufacture has presented many challenges. These include product instability, low yields and high levels of immunogenicity, with researchers continuing to employ many different strategies to address these various issues. A range of structural formats have been developed, each bringing differences in properties such as pharmacokinetic half-life, geometry of antigen binding sites and effector functions, while a multitude of expression systems has been explored.
At least thirty bispecific antibodies are currently in clinical development, with many more being progressed. These are mainly for oncology, autoimmune or chronic inflammatory indications although additional therapeutic applications of bsAbs are anticipated as our understanding of these molecules continues to grow. Beyond bsAbs we can expect to see the advancement of Zybodies, monoclonal antibody therapeutics with multiple specificities, however bsAbs appear to be an important and emerging therapeutic class which is rapidly becoming more widely known.