Bispecific antibodies: design, therapy, perspectives

Sedykh, Sergey E; Prinz, Victor V; Buneva, Valentina N; Nevinsky, Georgy A

In a short time, one may expect the completion of clinical trials and approval of BsAbs directed to treat autoimmune and other diseases. For example, promising results can be obtained in anti-HIV BsAbs. It has been shown that BsAbs directed against the CD4-and V3-binding sites on the Env (gp120) protein exhibit a synergistic effect in vivo and in vitro. Other variants of anti-HIV BsAbs combine antigenbinding sites against gp41, CD4, or CCR5 protein, and can be used to prevent HIV infection. 124, 125 The design of bispecific molecules demands analysis of the required BsAb properties (affinity to target molecules, pharmacokinetics in blood, and near target cells) and mechanisms of action. The increasing number of therapeutic BsAbs entering clinical trials and results of BsAb use in clinical medicine may improve understanding of their pharmacokinetics in the near future. The ideal therapeutic BsAbs are expected to have a long half-life in human blood, distribution among organs, and sufficient penetration of tissue. 126 The use of BsAbs in diagnostic tools is very promising, since BsAbs simplify the detection of target antigens. BsAbs are used in sensitive immunoassays developed for simple and rapid detection of bacterial and viral infectious diseases and in cancer diagnostics. 127 BsAbs significantly enhance the quality and reliability of in vivo cancer-diagnostic imaging by positron-emission tomography. The use of BsAbs and 131 I-labeled haptens allows pretargeting human prostate cancer xenografts in severe combined immunodeficient mice. With minimal signal background and high sensitivity and specificity, the use of BsAbs in this method is superior to mAbs. 128 Lipoarabinomannan is present in the blood of tuberculosis patients and is considered as a disease marker. The BsAb specific to lipoarabinomannan and horseradish peroxidase was developed with quadroma technology. The use of immunoswabs has shown 100% specificity and 64% sensitivity compared with bacterial cultures. Results were obtained within 2 hours of sample collection, which is very competitive compared to the standard laboratory-culture method, where results are obtained 2-6 weeks after sampling. 129 The use of anti-HBsAg × antihuman erythrocyte BsAbs allows detection of hepatitis B with 100% specificity and 97.7% sensitivity. The method can be used in actively infected patients since the serum HBsAg detection level ranges from 5 ng/mL to 600 μg/mL. 130 The quadroma expressing BsAbs against Escherichia coli lipopolysaccharide and whole bacteria in combination with horseradish peroxidase was used for rapid one-step sandwich enzyme-linked immunosorbent-assay detection of the E. coli strain O157:H7. The sensitivity of the detection was 100 CFU/mL and specific, since it did not detect Salmonella, Pseudomonas, or nonpathogenic E. coli. 131 The same approach was used for Bordetella pertussis detection. A quadroma producing anti-B. pertussis lipopolysaccharide and anti-horseradish peroxidase BsAbs was constructed for ultrasensitive immunoassay. 132 A similar method was developed for BsAbs detection of Staphylococcus aureus. The assay is highly sensitive and specific, due to release of a bound fluorescent reporter from a BsAb-active center after binding to the thermonuclease-specific antigen of S. aureus. 133 BsAbs recognizing several epitopes of the NP antigen of SARS coronavirus (causing severe acute respiratory syndrome) and binding to horseradish peroxidase were used for immunoswab