Antibody Fusion Proteins: Anti-CD22 Recombinant Immunotoxin … · chain proteins, making them more amenable for construc-tion of recombinant chimeric proteins (14). Recombinant immunotoxins

Antibody Fusion Proteins: Anti-CD22 RecombinantImmunotoxin Moxetumomab Pasudotox

Robert J. Kreitman and Ira Pastan

AbstractRecombinant immunotoxins are fusion proteins that contain the cytotoxic portion of a protein toxin fused

to the Fv portion of an antibody. The Fv binds to an antigen on a target cell and brings the toxin into the cell

interior, where it arrests protein synthesis and initiates the apoptotic cascade. Moxetumomab pasudotox,

previously calledHA22orCAT-8015, is a recombinant immunotoxin composedof the Fv fragment of an anti-

CD22 monoclonal antibody fused to a 38-kDa fragment of Pseudomonas exotoxin A, called PE38. Moxe-

tumomab pasudotox is an improved, more active form of a predecessor recombinant immunotoxin, BL22

(also calledCAT-3888),whichproducedcomplete remission in relapsed/refractoryhairy cell leukemia (HCL),

but it had a <20% response rate in chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia

(ALL), diseases inwhich the leukemic cells containmuch lower numbers ofCD22 target sites. Comparedwith

BL22,moxetumomabpasudotox is up to 50-foldmore active on lymphoma cell lines and leukemic cells from

patients with CLL and HCL. A phase I trial was recently completed in HCL patients, who achieved response

rates similar to those obtained with BL22 but without dose-limiting toxicity. In addition to further testing in

HCL, moxetumomab pasudotox is being evaluated in phase I trials in patients with CLL, B-cell lymphomas,

and childhood ALL. Moreover, protein engineering is being used to increase its activity, decrease nonspecific

side effects, and remove B-cell epitopes. Clin Cancer Res; 17(20); 6398–405. �2011 AACR.

Introduction

Targeted toxinsDifferent approaches have been used and are under

development to target toxic molecules to cancer cells andkill them more efficiently than would be possible withmonoclonal antibodies (mAb) alone. Radioimmunother-apy is the most established of these approaches, repre-sented by the approved drugs ibritumomab tiuxetan andtositumomab (1), and reviewed in this issue by Steinerand Neri (2). Exciting advances have been made withantibody-drug conjugates (3), particularly trastuzumabemtansine (4), SGN-35 (brentuximab vedotin; ref. 5),SAR3419 (6), and calicheamicin conjugates (7). Cyto-kines fused to antibodies are being used to attractimmune effector cells to cancer cells (8). Immunotoxinsare a type of antibody-conjugate in which a powerfulprotein toxin instead of a low-molecular-weight drug isattached to an antibody or antibody fragment. Theirpossible advantages include a very high activity, which

enables them to kill cells with relatively few target sites,and a unique mechanism of action that can bypass sometypes of drug resistance. This review focuses on recom-binant immunotoxins targeted to CD22, particularlymoxetumomab pasudotox.

Protein toxinsProtein toxins produced by bacteria, fungi, and plants are

extremely cytotoxic and can kill cells when only one or a fewmolecules reach the cytosol (9–12). These agents act byinhibiting protein synthesis and inducing apoptosis. Thebacterial toxinsPseudomonas exotoxinA (PE) anddiphtheriatoxin (DT) catalytically inactivate elongation factor 2 byADP ribosylation (9, 10). Plant toxins inactivate ribosomesby removing adenine4324 in 28s ribosomal RNA (11, 13).Unlike plant toxins, bacterial toxins are made as single-chain proteins, making them more amenable for construc-tion of recombinant chimeric proteins (14). Recombinantimmunotoxins are produced by replacing the bindingdomain of the toxin with the Fv portion of an antibodythat directs the toxin to a cancer cell. Target choice is veryimportant to prevent killing of normal cells. The lineage-restricted differentiation B-cell antigen CD22 is an excellenttarget because it is absent on normal tissues like liver andskin, and its lack of expression on B-cell precursors allowsnormal CD22þ B cells to be rapidly generated after immu-notoxin therapy ceases.

CD22, a sialic acid–binding immunoglobulin-like lectin(siglec) that inhibits B-cell receptor calcium signaling, isexpressed onmany B-cell malignancies, including hairy cell

Authors' Affiliation: Laboratory of Molecular Biology, National CancerInstitute, NIH, Bethesda, Maryland

Corresponding Author: Robert J. Kreitman, Laboratory of MolecularBiology, National Cancer Institute, NIH, 37/5124b, 9000 Rockville Pike,Bethesda, MD 20892. Phone: 301-496-6947; Fax: 800-864-7554; E-mail:[email protected]

doi: 10.1158/1078-0432.CCR-11-0487

�2011 American Association for Cancer Research.

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Clin Cancer Res; 17(20) October 15, 20116398

on December 3, 2020. © 2011 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from

http://clincancerres.aacrjournals.org/

leukemia (HCL), chronic lymphocytic leukemia (CLL),B-cell non-Hodgkin lymphoma (NHL), and acute lym-phoblastic leukemia (ALL; ref. 15). To kill these cells, weinitially constructed an immunotoxin that reactswithCD22by chemically conjugating a toxin fragment of PE to the LL2antibody (16). In studies with this immunotoxin as well asseveral other chemical conjugates, we found that theseconjugateswere heterogeneous in composition anddifficultto produce. Therefore, we turned to recombinant DNAtechniques to make recombinant immunotoxins, whichare stable,�60- to 65-kDa, homogeneous chimeric proteinsin which the Fv of a mAb is fused to truncated PE. Thechimeric gene encoding the recombinant immunotoxin isintroduced into Escherichia coli, where the recombinantprotein is produced.

Cellular intoxication by recombinant immunotoxinsCrystallographic studies have shown that PE is made up

of 3major structural domains (Fig. 1). Domain Ia is the cell-binding domain, domain II contains a furin site that is

necessary to release domain III from the cell-bindingdomain, and domain III contains the ADP-ribosylatingactivity that inactivates elongation factor 2. Domain Ib,which has no known function, can be partially or totallyremoved without affecting toxin activity. In recombinantimmunotoxins targeting CD22, domain Ia of PE is removedand replaced by the Fv portion of an antibody reacting withCD22 as shown in Fig. 1.

For cancer treatment, the recombinant immunotoxinis administered i.v. so that it can reach all of the cells. Afterinjection, the Fv at the amino terminus binds to CD22present on the B-cell malignancy being targeted (17),and the carboxyl terminal lysine residue at position 613(18) is rapidly removed by plasma carboxypeptidase,generating a protein ending in REDL. Very soon afterbinding, the recombinant immunotoxin-CD22 complex isinternalized through clathrin-coated pits into the endocyticcompartment (19), where 2 steps occur: (i) reduction of thedisulfide bond in domain II, and (ii) a furin-catalyzedcleavage in the middle of domain II, resulting in the

Figure 1. Intoxication of cells by moxetumomab pasudotox. Left, illustration of the structure of PE, PE38, and recombinant immunotoxin moxetumomabpasudotox designed to kill CD22-expressing cells. Right, cartoon showing the steps required for the entry and cell killing by moxetumomab pasudotoxand similar recombinant immunotoxins containing PE38. After internalization, PE undergoes proteolysis and disulfide-bond reduction to separatethe catalytic domain III from the binding domain Ia (20, 60, 61). PE38 undergoes both removal of the carboxyl terminal lysine residue (18) and processingbetween residues 279 and 280, resulting in a 37-kDa carboxyl terminal toxin fragment ending in the residues REDL. This fragment is believed to betransported intracellularly via the KDEL receptor from the Golgi to the endoplasmic reticulum (ER; 21), where it translocates to the cytosol, resulting inADP-ribosylation of elongation factor 2 (9), leading to apoptotic cell death (25).

Anti-CD22 Recombinant Immunotoxins

www.aacrjournals.org Clin Cancer Res; 17(20) October 15, 2011 6399



separation of the Fv from domain III (Fig. 1; ref. 20). TheREDL sequence at the carboxyl terminus of the protein thenbinds to the KDEL recycling receptor (21), and the ADP-ribosylating domain is transported to the endoplasmicreticulum, from which it translocates to the cytosol (22,23). Once in the cytosol, the toxin catalyzes ADP ribosyla-tion of the diphthamide residue (24) in EF-2 (9). This leadsto a rapid decrease in the levels of the antiapoptotic proteinMcl-1 and,with the assistance of BAK, initiates the apoptoticcascade (25–29).

Development of recombinant immunotoxins for CD22malignancies

The first recombinant immunotoxin that was designed tokill CD22-expressing cells contained a single-chain Fv of theanti-CD22 RFB4 antibody, which had been previouslyisolated by Peter Amlot in England, fused to PE38 (Fig. 1and Fig. 2). This recombinant immunotoxin had relativelymodest cytotoxic activity, with IC50s of 2 to 30 ng/mL,which we attributed to the instability of the 2 variabledomains linked by the (G4S)3 peptide (30). To increasestability, we introduced cysteine residues into the light andheavy chains of the Fv so that a disulfide bond would formand stably anchor the light and heavy chains instead of thepeptide linker that is used in most single-chain Fvs (Fig. 2;refs. 31–36). This protein was named BL22, for B-cellleukemia/lymphoma/CD22 (37).

Development of BL22In preclinical studies, BL22was cytotoxic to awide variety

of CD22-expressing cell lines, being 1.5- to 6.7-fold morecytotoxic than the single-chain recombinant immunotoxin(30, 37). BL22 induced complete remission (CR) in nudemice bearing CD22þ lymphoma xenografts at plasma levels

that could be safely achieved in cynomolgus monkeys (38).Primary ALL, CLL, andNHL cells were also tested ex vivo andfound to be sensitive to BL22 (39). CLL with as few as 350CD22 sites/cell could be killed (39). Thus, the preclinicaldata justified the testing of BL22 in humans. A GoodManufacturing Practices lot of BL22 was produced at theMonoclonal Antibody and Recombinant Protein facility ofthe National Cancer Institute, and clinical trials were initi-ated in 1999.

Phase I–II activity of BL22In the phase I trial, we elected to give BL22 every other day

(QOD), for a total of 3 doses per cycle, and to repeat cyclesevery 21 to 28 days. The QOD dosing was based on animalexperiments that showed that toxicity generally occurswithin 48 hours of each dose. Therefore, keeping the dosinginterval to 2 days in patients may prevent cumulativetoxicity, particularly during dose escalation. In targetingHCL, where high CD22 density represents a sink for thedrug, this dosing interval had an additional advantage inallowing dying cells to clear prior to the next dose.Webeganat 3 mg/kg and determined the maximum tolerated dose(MTD) to be 40 mg/kg � 3. In total, we treated 46 patientswho had experienced failure of standard therapies for theirdisease, including 31 with HCL, 4 with B-NHL, and 11 withB-CLL (40, 41). In the 31 patients with HCL, 19 CRs (61%)and 6 partial remissions (PR; 19%) were achieved, for anoverall response rate (ORR) of 81%. A hemolytic uremicsyndrome composed of thrombocytopenia, hemolytic ane-mia, and renal insufficiencywas observed in 4HCLpatients,and it completely resolved after 6 to 10 days of plasmaphe-resis. Dose-limiting capillary leak syndrome (CLS) was lesscommon, appearing in only 1 HCL patient. Pharmacoki-netic analysis of BL22 showed a strong sink effect of CD22

Figure 2. Recombinantimmunotoxins in use or underdevelopment. BL22 was reported in1997 (37) as RFB4(dsFv)-PE38 andwas later called CAT-3888. VL andVH are disulfide-bonded togetherusing engineered cysteine residuesreplacing Arg44 of VH and Gly100 ofVL. In 2002, BL22 was mutated toHA22 (later called CAT-8015 andmoxetumomab pasudotox) bychanging SSY to THW at positions100, 100a, and 100b of VH(45; horizontal redbars). In 2009, thedeletion mutant HA22-LR wasreported where PE amino acids251–394 were replaced by aminoacids 274–284 containing the Furincleavage site (50). Most recently(in 2011), HA22-LR-8M, a mutant ofHA22-LR, was reported to contain 8mutations: D406A, R432G, R467A,R490A, R513A, E548A, K590S, andQ592A (59).

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in HCL during the first cycle, caused by disease burden andhigh levels of soluble CD22, both of which decreased withresponse (42). Because 65% of CRs occurred after just 1cycle of BL22, the phase II trial was planned to limit BL22 to1 cycle and re-treat only those patients who had notachieved recovery of cytopenias to the level needed for CR.In 36 phase II patients receiving 1 cycle of BL22 at 40 mg/kgQOD� 3, there were 9 CRs (25%) and 9 PRs (25%), for anORR of 50%. With selective re-treatment of 56% of thepatients, the final ORR increased to 72%, including 47%CRs (43). Themedian time to relapse of cytopenias had notbeen reached after nearly 7 years of follow-up. This indi-cated significant activity in relapsed/refractory HCL with asafety profile supporting continued development. Howev-er, because the activity of BL22wasmuch lower inCLL, ALL,and NHL than in HCL (41, 44) and activity in the more-common malignancies was essential for commercial devel-opment,wehad to switch our clinical efforts to an improvedimmunotoxin.

Development of moxetumomab pasudotox, anaffinity-matured version of BL22An important variable in the activity of immunotoxins is

their affinity for the target antigen, which determines howmuch immunotoxin will bind to a target cell at any givenconcentration and how long the cell-bound immunotoxinwill remainon the cell surface. The longer it stays attached tothe target protein (CD22), the more likely it is to enter andkill the target cell. BL22 has a moderate affinity for CD22(Kd �10 nmol/L). This affinity is sufficient to kill enoughHCL cells in patients to achieveCR.HCL cells have amedianof �40,000 CD22 sites per cell, ranging from 10,000 to>100,000. However, BL22 was much less effective in chil-drenwith ALL (4,500 sites/cell) or CLL (1,200 sites/cell). Toimprove the affinity and activity of BL22, we carried outmutagenesis studies and selected an Fv with a higher bind-ing affinity by antibody phage display. Mutation of 3residues inCDR3of theheavy chainof theBL22Fv (residues100, 100a, and100b) fromSSY to THW increased affinity by�15-fold and cytotoxicity toward HCL and CLL cells by up

to 50-fold (45). The improvement in binding affinity wasdue to a slowing of the off rate, which led to increasedcytotoxicity and antitumor activity despite similar pharma-cokinetics and animal toxicity (46). Thenew, higher-affinityversion of BL22 was initially named HA22 (high-activityBL22). Later, after it was licensed to Cambridge AntibodyTechnologies, it was named CAT-8015, and it is now beingdeveloped by MedImmune as moxetumomab pasudotox.

Phase I testing of moxetumomab pasudotoxAt the 2010 American Society of Hematology Annual

Meeting (Orlando, FL; December 4–7, 2010), interimresults were reported for clinical trials with moxetumomabpasudotox in HCL and ALL. Clinical trials are listed inTable 1. Several striking differences between moxetumo-mab pasudotox and BL22 have been noted. One is that inthe HCL trial, dose-limiting toxicity was not observed anddose escalation was terminated at 50 mg/kg, a dose levelabove the MTD for BL22, because response rates were highat all dose levels. In fact, theORR froman interimanalysis ofmoxetumomab pasudotox, 79% (47), was similar to the72% ORR reported from the phase II study of BL22 (43).Another striking finding is that 3 responses (all CRs) wereobserved in 12 patients with pediatric ALL (48), represent-ing the first time responses of thismagnitude were observedwith this type of agent in this aggressive disease.

Interim phase I results in HCLAt the 2010 American Society of Hematology Annual

Meeting (49), investigators presented findings obtainedfrom 32 patients with refractory HCL, all of whom hadreceived 2 ormore prior courses of purine analogue therapyand needed treatment based on established criteria for HCL(i.e., neutrophils < 1000/mm3, platelets < 100,000/mm3,hemoglobin < 10 g/dL, or symptomatic splenomegaly).Patients received dose levels of 5 to 50 mg/kg QOD � 3 ina standard dose-escalation phase, with cycles repeated every4 weeks. Patients were re-treated until they reached 2 cyclespast CR; however, treatment was stopped earlier if progres-sive disease or immunogenicity was detected. Surprisingly,

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, unlessresponse to first course was <2 years

NIH

CLLa �2 prior therapies, �1 with rituximab NIH, SCRI, IU, MUSC, CCCN, CSMCDLBCL, MCL �1 prior therapy with rituximabFL �2 prior therapies, �1 with rituximabALL (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 CancerInstitute; DLBCL, diffuse large B-cell lymphoma; HSCT, hematopoietic stem cell transplant; IU, Indiana University; MCL, mantlecell lymphoma; MUSC, Medical University of South Carolina; SCRI, Sarah Cannon Research Institute; SJ, Saint Jude Children'sResearch Hospital.aListed as a phase I–II trial.





no dose-limiting toxicity was observed in the 32 patients,despite the fact that half of the patients enrolled (n ¼ 16)were at the 50 mg/kg � 3 dose level, which was higherthan the MTD of BL22 (41). The most common adverseevents, seen in 20% to 50% of patients, were expected fromprior experience with immunotoxins. These included mildCLS causing weight gain, hypoalbuminemia, peripheraledema, fever, elevated transaminases, fatigue, and head-ache. The only evidence of possible hemolytic uremic

syndrome was asymptomatic laboratory abnormalitiesin 2 patients, with peak creatinine of 1.53 to 1.66 mg/dLand platelet nadir of 111,000 to 120,000/mm3. Majorresponses were observed at all dose levels in the 32 patientsreported, with CRs observed at all dose levels from 10to 50 mg/kg QOD � 3, and the CR rate at all doses was31% at the time of interim analysis. The median time toresponse was 2.8 months (49). Only 1 of the 14 patientswho achieved CR relapsed in less than 1 year, indicating

Moxetumomab pasudotox

HA22-LR

R490

R432

R467R513

E548

Q592

D406K590

HA22-LR-8M

Figure 3. Structure of HA22-LR-8M.Ribbon structures show thelocations of the mutations inHA22-LR-8M and the deletion fromHA22 used in HA22-LR andHA22-LR-8M. Adapted from Ondaet al. (59).

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that responses were durable. In summary, moxetumomabpasudotox showed high and durable antitumor activity inpatients with relapsed/refractory HCL, statistically similartoBL22butwithout dose-limiting toxicity, justifying furtherclinical development toward the goal of approval for thisdisease. Moxetumomab pasudotox is also being evaluatedin CLL and B-cell lymphomas, but data are not yet availablefrom those trials.

Interim phase I results in ALLBecause pediatric ALL is a much more rapidly growing

and aggressive disease than HCL, patients were treated withmoxetumomab pasudotox QOD for 6 doses, and the cycleswere repeated every 21 days (48). A rapid dose-escalationschemewas used for the lowdose levels (5, 10, and 20mg/kgQOD � 6), and then a standard dose escalation began at30 mg/kg QOD � 6. Fourteen patients 5 to 22 years of age(median, 11 years) were enrolled in the trial. All of thesepatients had been heavily pretreated with 2 to 8 (median 4)prior regimens, and 7 had previously undergone stemcell transplantation. Common toxicities included elevatedbilirubin, transaminases, and creatinine, and CLS in-cluding hypoalbuminemia, proteinuria, hypoxia, and pleu-ral effusion. Grade 3/4 CLS was observed in 2 of the first7 patients (both treated at 30 mg/kg QOD � 3) but not in7 subsequent patients once dexamethasone prophylaxiswas instituted. As mentioned above, of 12 patients whowere evaluable for response, 3 (25%) achieved CR after 1to 2 cycles, and 5 (42%) had hematologic improvementwith reduction in circulating blasts. As in the HCL trial,CRs were observed at dose levels as low as 10 mg/kg. Thus,moxetumomab pasudotox has achieved major responses,including CRs, in patients with ALL. Due to the aggressivenature of the disease and the young age of these patients,even a transient CR can be lifesaving as a bridge to trans-plantation. Further clinical development ofmoxetumomabpasudotox is proceeding in ALL to determine whetherhigher dose levels and more frequent dosing can improveresponses.

A Protease-Resistant Moxetumomab Pasudotox

One impediment to the cytotoxic activity of immuno-toxins is that many of the immunotoxin molecules thatenter target cells do not reach the endoplasmic reti-culum and cytosol; instead, they are transferred to lyso-somes and other compartments containing lysosomalenzymes, where they are inactivated by proteolysis (Fig. 1).To identify potential lysosomal protease cleavage sites,investigators treated recombinant immunotoxins with lyso-somal enzymes and identified the cleavage sites by aminoacid analysis (50). These studies revealed that all of themajor protease sites were clustered in domain II and couldbe removed, leading to a new lysosomal protease-resistantimmunotoxin named HA22-LR (Fig. 2 and Fig. 3). InHA22-LR, all of domain II is deleted except for the 11 aminoacids that make up the essential furin-processing site.HA22-LR had several useful properties, including increased

activity, particularly on CLL cells, where HA22-LR had amedian 16-fold improved cytotoxic activity comparedwith HA22 and more than 10-fold reduced nonspecifictoxicity to mice (50). The latter finding may be due to lossof residues that interact with endothelium or macrophagesand produce liver damage in mice and possibly CLS inother animals, including humans (50–53). It is possiblethat the smaller size of HA22-LR (51.0 kDa versus63.3 kDa for HA22) may allow improved tumor penetra-tion. Finally, because we could safely give much higherdoses to mice, we were able to achieve much better anti-tumor activity (50).

A Moxetumomab Pasudotox Variant with NoImmunogenicity in Mice

Although the incidence of antibody formation inpatients treated with moxetumomab pasudotox is lowand did not prevent CRs in HCL and ALL, furtherdecreases in toxin immunogenicity remain an importantgoal. For patients with solid tumors and normal immunesystems, immunogenicity rates of 80% to 90% wereobserved after 1 cycle of 3 doses (54–56). To deimmunizethe toxin, efforts to identify and remove both T-cell (57)and B-cell (58) epitopes are underway. To date, moreprogress has been made with the B-cell epitope approach(53, 59). On the basis of the hypothesis that human andmouse B-cell epitopes are similar, we used mice for thesestudies and identified 7 major epitopes in PE38: 3 indomain II, and 4 in domain III. The epitopes in domain IIare removed in HA22-LR (50), which has a deletion ofmost of domain II, and the epitopes in domain III weredestroyed by mutating 8 different bulky amino acids toalanine, serine, or glycine to produce HA22-LR-8M (59).We measured the reactivity of HA22-LR-8M with serumfrom patients who made antibodies to HA22, and wefound that reactivity with antisera was greatly decreasedbut not abolished. We are now engaged in studies toidentify and remove the remaining human-specific epi-topes. Our data suggest that new immunotoxins withlow immunogenicity will not be needed for the success-ful treatment of B-cell malignancies, because the immunesystem is very suppressed. However, they will be usefulfor the treatment of solid tumors, where neutralizingantibodies develop in the vast majority of patients after1 cycle of 3 doses. For HCL in particular, we believethe clinical results (both efficacy and safety profile) formoxetumomab pasudotox justify further clinical devel-opment, including a pivotal phase III trial currentlyunder design, with the goal of achieving U.S. Food andDrug Administration approval for the use of moxetumo-mab pasudotox for this disease.

Disclosure of Potential Conflicts of Interest

I. Pastan is an inventor on patents on moxetumomab pasudotoxheld by the NIH. The authors disclose no other potential conflicts ofinterest.





Acknowledgments

The authors thank the members of our current clinical team, Rita Min-cemoyer, Elizabeth Maestri, Natasha Kormanik, Barbara Debrah, and SonyaDuke. We also thank our research team and collaborators Inger Margulies,Hong Zhou, Evgeny Arons, David FitzGerald, Alan Wayne, Richard Beers,JohnWeldon, Laiman Xiang, Byungkook Lee, andMasanori Onda. Principalinvestigators for the ALL trial included Drs. Alan Wayne, Deepa Bhojwani,and Lewis Silverman, and principal investigators for the HCL trial includedDrs. Martin Tallman, Steven Coutre, and Tadeusz Robak.

Grant Support

National Cancer Institute Intramural Program; development ofBL22 and moxetumomab was supported in part by MedImmune,LLC.

Received April 12, 2011; revised July 28, 2011; accepted July 29, 2011;published online October 14, 2011.

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2011;17:6398-6405. Clin Cancer Res Robert J. Kreitman and Ira Pastan Moxetumomab PasudotoxAntibody Fusion Proteins: Anti-CD22 Recombinant Immunotoxin

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Antibody Fusion Proteins: Anti-CD22 Recombinant Immunotoxin … · chain proteins, making them more amenable for construc-tion of recombinant chimeric proteins (14). Recombinant immunotoxins