Bispecific antibodies: design, therapy, perspectives

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

Sedykh et al detail in many reviews. [37] [38] [39] [40] [41] [42] Catumaxomab is produced using the "quadroma" technology: HL fragments of mouse mAbs against CD3 (IgG 2a ) and rat mAbs (IgG 2b ) against EpCAM secreted by the corresponding hybridomas are combined in one bispecific molecule, which also binds the Fc-receptor. 43 The Fc of catumaxomab preferentially binds to FcγRI, FcγRIIa, and FcγRIII activation receptors, but not to the FcγRIIb inhibitory receptor. This determines the recruitment and activation of macrophages, NK cells, and dendritic cells (FcγR + ), leading to a complex immunoreaction. 40 The use of HL fragments obtained from different host organisms reduces the possibility of BsAb formation with mismatched light chains, since light chains of rat Abs predominantly interact with rat heavy chains, and vice versa; light chains of mouse Abs are preferably associated with heavy mouse chains. 43 The application of catumaxomab in clinical trials and therapy proves to be successful, since there is no barrier for T lymphocytes or catumaxomab molecules to penetrating ascites tumors. Ascites tumors are represented by separate cells that float separately from one another in liquid, which unites them with lymphoma and leukemia, two other liquid tumors, against which is directed blinatumomab. As in the case of blinatumomab, the antitumor effect of catumaxomab is due to the colocalization of a T-lymphocyte, of a tumor cell expressing EpCAM, and of the cell with the Fc receptor on the surface (macrophage, dendritic cell, natural killer) ( Figure 2 ). Therefore, catumaxomab enhances activation of the patient's immune system against the tumor. Binding of catumaxomab to Fcγ receptors of antigen-presenting cells turns inflammatory monocytes to express costimulatory molecules, which are necessary for T-cell activation. 44, 45 During preclinical studies, it was shown that catumaxomab could provide immunoresponse due to B-and T-memory cells activated by the Fc receptor. 46 In a Phase IIIB clinical trial, intraperitoneal infusion of catumaxomab favored accumulation of and activated macrophages, NK cells, and CD4 + and CD8 + T-cells in ascites of peritoneal cavities. 47, 48 The interaction of patient immune cells with tumor cells leads to a complicated reaction, resulting in the elimination of tumor cells. Studies have shown several mechanisms of cytotoxicity: lymphocyte-mediated lysis, cytokine action (IL1β, IL2, IL6, IL12, CCL18 chemokine), phagocytosis, and Ab-dependent cellular toxicity. Compared to BsAbs, individual mouse and rat mAbs (anti-CD3 and anti-EpCAM) show significantly lower antitumor potential. 37 Catumaxomab has high therapeutic potential with acceptable safety: intraperitoneal administration of low doses (10-100 mg) of the drug are carried out four to five times with an interval of 10-14 days. Catumaxomab is approved for the treatment of malignant ascites and is currently undergoing clinical trials in ovarian, stomach, and epithelial cancer. At the same time, a similar therapeutic effect is observed in some other tumors, eg, in ovarian carcinoma, catumaxomab reduces the formation of ascitic fluid. 49 Interestingly, one of the catumaxomabtherapy side effects is the formation of Abs against mouse and rat Abs, and notably immunoresponse against mouse Abs correlates with positive response to treatment. 50