Bispecific Antibody: A Rising Star in Tumor Immunotherapy Filed

Bispecific antibody (BsAb) is an artificially engineered antibody that can simultaneously bind two specific epitopes or target proteins with some special biological functions, such as directly targeting effector cells to tumor cells, to enhance cytotoxicity, improve antibody selectivity and functionality, and avoid immune escape mechanisms, thereby improving therapeutic efficacy. BsAb also reduces the cost of drug development and clinical trials compared to the combination of two monoclonal antibody drugs.

Owing to these unique abilities, bispecific antibodies turn out to be an effective approach to tumor immunotherapy. At the same time, bispecific antibodies production can be combined with other drugs, such as drugs for cell cycle control and indoleamine dioxygenase inhibitors, which are beneficial to improve the efficacy. Up to now, there are more than one hundred BsAbs including those that have been listed and those in R&D process, such as Catumaxomab, Blinatumomab.

Catumaxomab (Removab, Trion) was formally approved by EMA in 2009 for marketing in Europe for the treatment of malignant ascites, a common complication in patients with advanced stage of abdominal metastatic cancer and became the first bispecific antibody to be marketed worldwide. It is a trifunctional antibody with a molecular weight of 150 kDa consisting of a mouse IgG2a targeting tumor EpCAM and a rat IgG2b targeting CD3ε, while also activating monocytes, macrophages, stellate cells, and NK cells via Fcγ receptors. In phase II/III studies, catumaxomab improved puncture-free survival and median time to next paracentesis, reduced signs and symptoms of ascites, and showed a trend toward improved OS. Although Catumaxomab was the first bispecific antibody approved for marketing, it also has some significant limitations, mainly reflected in the complex production process of Triomab antibody and the immunogenicity problems easily generated by heterologous antibodies.

Blinatumomab was another influential BsAb approved in 2014 for the treatment of Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (ALL). It is a bispecific single-chain antibody, BiTE, produced using DNA recombination technology that links the variable regions of two monoclonal antibodies targeting tumor cells and T cell surface antigens through a polypeptide chain. Blinatumomab selectively targets the B cell surface antigen CD19 and specifically binds the T cell surface antigen CD3 to activate T cells. Because it is mainly composed of two scFv junctions, BiTE has a small molecular weight (55 – 60 kDa) and easily permeates tumor tissues. BiTE also lacks the Fc portion and is therefore less immunogenic. Clinical trials have demonstrated that blinatumomab, even at very low doses, is effective in recruiting T cells and eliminating tumors, significantly improving median overall survival (OS) in patients with relapsed or refractory B-cell precursor ALL. However, it also has some common adverse effects including fever, headache, febrile neutropenia.

In the future, the bispecific antibody targeting new targets are required for the sake of novel anti-tumor drugs development with less side effects that increase target specificity in order to reduce killing effects on non-tumor cells. Meanwhile, a more effective combination of target BsAbs instead of the traditional random combination is expected for a higher recovery and lower drug cost.