Article Figures & Data
Figures
- Figure 1.
Intoxication of cells by moxetumomab pasudotox. Left, illustration of the structure of PE, PE38, and recombinant immunotoxin moxetumomab pasudotox designed to kill CD22-expressing cells. Right, cartoon showing the steps required for the entry and cell killing by moxetumomab pasudotox and similar recombinant immunotoxins containing PE38. After internalization, PE undergoes proteolysis and disulfide-bond reduction to separate the catalytic domain III from the binding domain Ia (20, 60, 61). PE38 undergoes both removal of the carboxyl terminal lysine residue (18) and processing between residues 279 and 280, resulting in a 37-kDa carboxyl terminal toxin fragment ending in the residues REDL. This fragment is believed to be transported intracellularly via the KDEL receptor from the Golgi to the endoplasmic reticulum (ER; 21), where it translocates to the cytosol, resulting in ADP-ribosylation of elongation factor 2 (9), leading to apoptotic cell death (25).
- Figure 2.
Recombinant immunotoxins in use or under development. BL22 was reported in 1997 (37) as RFB4(dsFv)-PE38 and was later called CAT-3888. VL and VH are disulfide-bonded together using engineered cysteine residues replacing Arg44 of VH and Gly100 of VL. In 2002, BL22 was mutated to HA22 (later called CAT-8015 and moxetumomab pasudotox) by changing SSY to THW at positions 100, 100a, and 100b of VH (45; horizontal red bars). In 2009, the deletion mutant HA22-LR was reported where PE amino acids 251–394 were replaced by amino acids 274–284 containing the Furin cleavage site (50). Most recently (in 2011), HA22-LR-8M, a mutant of HA22-LR, was reported to contain 8 mutations: D406A, R432G, R467A, R490A, R513A, E548A, K590S, and Q592A (59).
- Figure 3.
Structure of HA22-LR-8M. Ribbon structures show the locations of the mutations in HA22-LR-8M and the deletion from HA22 used in HA22-LR and HA22-LR-8M. Adapted from Onda et al. (59).
Tables
- Table 1.
Ongoing phase I trials with moxetumomab pasudotox
Diseases Prior therapy needed for eligibility Current location HCL ≥2 prior therapies, ≥2 purine analogue courses, unless response to first course was <2 years NIH CLLa ≥2 prior therapies, ≥1 with rituximab NIH, SCRI, IU, MUSC, CCCN, CSMC DLBCL, MCL ≥1 prior therapy with rituximab FL ≥2 prior therapies, ≥1 with rituximab ALL (pediatric) ≥2 prior therapies, prior HSCT allowed NIH, SJ, DF Abbreviations: CCCN, Comprehensive Cancer Center of Nevada; CSMC, Cedars Sinai Medical Center; DF, Dana-Farber Cancer Institute; DLBCL, diffuse large B-cell lymphoma; HSCT, hematopoietic stem cell transplant; IU, Indiana University; MCL, mantle cell lymphoma; MUSC, Medical University of South Carolina; SCRI, Sarah Cannon Research Institute; SJ, Saint Jude Children's Research Hospital.
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↵aListed as a phase I–II trial.
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Volume 17, Issue 20
