RFB4dsFvPE38 BL22

Figure 33.1 Structure of biologic salvage therapies in HCL. Rituximab is a chimeric anti-CD20 mAb containing the mouse variable domains (Vl and Vh) of the mAb 2B8 grafted to the human IgG1 constant domains (C and Ch1-Ch2-Ch3). Pseudomonas exotoxin (PE) contains 613 amino acids. Domain la (amino acids 1-252) is the binding domain, domain II (amino acids 253-364) is responsible for translocating the toxin to the cytosol, and domain Ill (amino acids 400-613) contains the ADP-ribosylating enzyme which inactivates elongation factor 2 (EF-2) in the cytosol. The function of domain lb (amino acids 365-399) is unknown. PE38 is a truncated form of PE devoid of domain la and amino acids 365-380 of domain lb. The single-chain recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) contains the variable heavy domain (Vh) of the anti-Tac mAb fused via the peptide linker (G4S)3 to the variable light domain (Vl), which in turn is fused to PE38. The recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) is composed of the Vl from the mAb RFB4 disulfide bonded to a fusion of Vh with PE38. The disulfide bond connecting Vh and Vl is formed between two cysteine residues replacing Arg44 of VH and Gly100 of VL

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