review article radioimmunotherapy: a specific...

Review ArticleRadioimmunotherapy A Specific Treatment Protocol forCancer by Cytotoxic Radioisotopes Conjugated to Antibodies

Hidekazu Kawashima

Department of Radiopharmaceutical Chemistry Faculty of Pharmaceutical Sciences Health Sciences University of Hokkaido1757 Kanazawa Tobetsu-cho Ishikari-gun Hokkaido 061-0293 Japan

Correspondence should be addressed to Hidekazu Kawashima kawashimahoku-iryo-uacjp

Received 27 June 2014 Accepted 4 August 2014 Published 14 October 2014

Academic Editor Masahiro Ono

Copyright copy 2014 Hidekazu Kawashima This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Radioimmunotherapy (RIT) represents a selective internal radiation therapy that is the use of radionuclides conjugated totumor-directed monoclonal antibodies (including those fragments) or peptides In a clinical field two successful examples of thistreatment protocol are currently extended by 90Y-ibritumomab tiuxetan (Zevalin) and 131I-tositumomab (Bexxar) both of whichare anti-CD20 monoclonal antibodies coupled to cytotoxic radioisotopes and are approved for the treatment of non-Hodgkinlymphoma patients In addition some beneficial observations are obtained in preclinical studies targeting solid tumors To datein order to reduce the unnecessary exposure and to enhance the therapeutic efficacy various biological chemical and treatmentprocedural improvements have been investigated in RIT This review outlines the fundamentals of RIT and current knowledge ofthe preclinicalclinical trials for cancer treatment

1 What Is Radioimmunotherapy (RIT)

Antibodies (Abs) are glycoproteins secreted from plasma Bcell and are used by immune system to identify and removeforeign pathogens such as bacteria and viruses Because itis considered that Abs also have cytotoxic potency againstsomemalignant tumor cells the therapeutic efficacy in cancerhas been examined However intact Abs are insufficient toimprove patient survival rate dramatically As a one approachto enhance the therapeutic response by using immunologicaltechnique cytotoxic radioisotopes (120572- or 120573-particle emitters)are conjugated to Abs or the fragments This strategy isemployed to deliver radioisotopes to the targeting tissue byappropriate vehicle After the radiolabeled Abs bind to recep-torstumor antigens expressed on the surface of canceroustissue cells within an anatomic region of the 120572- or 120573-rangewill be killed

In a clinical field systemic radiotherapy using nakedradioisotope (iodine-131 131I) was first performed by Hertzto patient of Gravesrsquo disease in 1941 [1] Then investigationson the use of Abs coupled with adequate radioisotopessubsequently emerged in the early 1950s [2 3]Though direct

radioiodinated Abs were mainly used in the initial clinicalstudies progress in chelation chemistry has enabled the uti-lization of many therapeutic metal radioisotopes that possessinherent radiation properties Various combinations of Absand radioisotopes have been examined which results in theadaptation in different clinical situations [4 5] RIT involvesthe application of radiolabeled monoclonal Abs (mAbs) tomolecular targeted therapy [6] Both the use of directlylabeled mAbs and in vivo label of tumor-binding mAbs byconjugation-pretargeting method have been developed

Irradiated cells absorb high amounts of energy in theform of photons or charged particles which promote thedirect macromolecular damage as well as the generationof reactive oxygen andor nitrogen species [7] Both freeradicals and molecular oxygen damage DNA strand [8 9]and the damage induces not only apoptosis [10] but alsoprogrammed necrosis [11] Because the ranges in tissue ofionizing radiations are rather large compared with a typicalcell size uniform binding of the radioimmunoconjugates isnot a prerequisite for its efficacy In other words adjacent cellsnot expressing the receptorstumor antigens can also be killed

Hindawi Publishing Corporatione Scientific World JournalVolume 2014 Article ID 492061 10 pageshttpdxdoiorg1011552014492061

2 The Scientific World Journal

Table 1 Radioisotopes used in RIT

Radioisotope Energymax (MeV) Range Half-life120573-Particle emitter

67Cu 058 21mm 26 d90Y 228 120mm 27 d131I 061 20mm 80 d177Lu 050 15mm 67 d186Re 107 45mm 37 d188Re 212 104mm 169 hr

120572-Particle emitter211At 68 80 120583m 72 hr213Bi 83 84 120583m 46min225Ac 60sim80 60sim90 120583m 100 d

Auger-electron emitter125I 2sim500 nm 605 d

by the physical cross-fire effect This means continuous low-dose irradiation from radiolabeled Abs cause lethal effectson nearby normal cells Moreover it is reported that RITsalso evoke the normalization of tumor vasculature [12]presumably owing to facilitation of immune cell migrationtowards the malignant lesions [13]

For therapy therefore120572- or120573-particle emitters are prefer-able Vehicles coupled with radioisotopes emitting Augerelectrons are also available however they need to be localizedclose to DNA due to the very short range of these radiations[14ndash16] Simultaneous emission of 120574 (X) rays which aresuitable for imaging will help measure pharmacokineticparameters and calculate dosimetry of the radioimmunocon-jugates Table 1 shows radioisotopes commonly used for RIT

Among them relatively well-studied and practicalradioisotopes are the 120573-emitters 131I yttrium-90 (90Y) andlutetium-177 (177Lu) Radioisotope to use is selected byconsideration of those radiophysical properties (energy andhalf-life) as well as the labeling chemistry For example 90Ypossesses a higher 120573-particle 119864max and a shorter half-lifewhen compared with 131I On the other hand metal 90Yshould be conjugated to Ab via chelating agent whereas 131Ican form a carbon-iodine bond directly Lutetium-177 hasradiophysical properties similar to 131I and radiolabelingchemistry similar to 90Y

Investigations of RIT using 120572-particle emitters also havebeen developed Because 120572-particle gives its energy to thesurrounding molecules within a narrow range (lt100120583mequivalent to a few cell diameters) it leads to high lin-ear energy transfer (high LET) within the target and lessbystander effect to nontarget tissues compared to Abs labeledwith 120573-emitters In addition to the high LET which leads tothe high relative biological effectiveness (RBE) [17] recentstudies have shown that cytotoxic efficacy of 120572-particle isindependent of the local oxygen concentration and cellcycle state [18] Bismuth-213 (213Bi) astatine-211 (211At)and actinium-225 (225Ac) are well investigated in 120572-particleRIT [19ndash22]

Compared to external beam radiation therapy one ofthe most potent advantages of RIT is the ability to attacknot only the primary tumor but also lesions systemicallymetastasizing In addition targeted radiotherapy using spe-cific vehicle agents is extremely valuable in cases of (1)residual micrometastatic lesions (2) residual tumor marginsafter surgical resection (3) tumors in the circulating bloodincluding hematologicmalignancy and (4)malignancies thatpresent as free-floating cells [23]

Brief data on current RITs provided in this review paperis summarized in Table 2

2 Direct Method

The success of RIT depends on the selective accumulation ofcytotoxic radioisotopes at affected areas Fundamental prop-erties required for vehicles against a particular biomarkerare (1) high binding affinity to the intended target (2) highspecificity (3) high tumor to background ratio (4) highmetabolic stability and (5) low immunogenicity [24 25]From the viewpoint of those molecular characteristics Abshave been considered as suitable agent for the delivery oftherapeutic radioisotopes Moreover the development ofhybridoma technology in 1975 allowed taking advantage ofmAbs in RIT [26]

ldquoDirect methodrdquo requires direct conjugation of cytotoxicradioisotopes to various antitumormAbs (or their fragments)via an appropriate chelator and the single-step administra-tion to patients Consequently many antigenic determinants(mostly on the cell surface) have been targeted byAbs On theother hand one of the most critical obstacles to achieve highbackground ratio in this application is the slow clearance ofAbs from the blood and nontarget tissues due to their highmolecular weight [27 28] Abs will disappear from plasmavery slowly which encourages higher tumor uptake howevera longer duration is needed to reach the maximum tumor tonormal radioactivity ratio Radiation dose for treating patientincreases time-dependently which results in the exposureof radioactive bone marrow leading to the hematologictoxicity Therefore structural diversification of Abs has beenattempted to improve the pharmacokinetic properties Lowermolecular weight fragments of conventional Abs includingF(ab1015840)

2 Fab or its multivalent conjugate minibody diabody

and single chain variable fragments (scFv) could be utilizedwhich retain the essential antigen binding properties andobtain more rapid clearance rates than intact mAbs Thosesmaller types of constructs can traverse the vascular channelsresulting in a more rapid tumor uptake and a faster bloodclearance than parental Abs [29 30] possessing potenciesto achieve superior tumor to background ratios In generalhowever affinities of small Ab forms to tumor antigen arelower than those of Abs and moreover too fast bloodclearance of peptides yields less time to interact with thetarget Therefore absolute tumor uptake for these constructsis lower than those of Abs Further development of theengineered forms holding both favorable pharmacokinetics

The Scientific World Journal 3

Table2AnticancerR

ITsreportedin

thiscentury

Cancer

Targetmolecule

mAb

Radioisotope

Subject

Reference

Dire

ctmetho

d

Non

-Hod

gkin

lymph

oma

CD20

Ibritum

omab

Y-90

Hum

an(in

clinicalu

se)

[33]

Tositum

omab

I-131

Hum

an(in

clinicalu

se)

[313334]

Rituximab

I-131

Hum

an(phase

II)

[35ndash37]

CD22

Epratuzumab

Y-90

Hum

an(phase

II)

[323839]

Myeloid

leuk

emia

CD33

Lintuzum

abBi-213

Hum

an(phase

II)

[4041]

RajiB-lymph

oma

CD74

L243

Ga-67

Cell

[42]

Colorectalcancer

Carcinoembryonica

ntigen

(CEA

)cT

8466

Y-90

Hum

an(phase

I)[5455]

A33

glycop

rotein

huA33

At-211

Mou

sexeno

graft

mod

el[62]

Colorectalcancer(liver

metastases)

CEA

F6F(ab1015840) 2

I-131

Hum

an(phase

II)

[58]

CEA-

related

celladhesio

nmolecule

Labetuzumab

I-131

Hum

an(phase

II)

[6364

]Gastro

intestinalcancer

CEA

A5B

7I-131

Hum

an(phase

I)[48]

Breastcancer

HER

-2Trastuzumab

Y-90

Mou

sexeno

graft

mod

el[66]

Pb-212

Hum

an(phase

I)[68]

NLS

-trastuzumab

In-111

Cell

[67]

Ovaria

ncancer

Na-depend

entp

hosphatetransporter

MX3

5F(ab1015840) 2

At-211

Hum

an(phase

I)[73]

Prostatecancer

MUC-

1m170

Y-90

Hum

an(phase

I)[7576]

J591

Y-90

Hum

an(phase

I)[77]

Lu-177

Hum

an(phase

I)[78]

Bi-213

Mou

sexeno

graft

mod

el[79]

Multip

lemyeloma

CD138

AntiC

D138Ab

Bi-213

Mou

sexeno

graft

mod

el[20]

Indirectmetho

d

Non

-Hod

gkin

lymph

oma

CD20

TF4(H

SG)

Y-90

Mou

sexeno

graft

mod

el[100101]

1F5(scFv) 4(stre

ptavidin)

Y-90

Mou

sexeno

graft

mod

el[102]

CD20C

D22H

LA-D

RCorrespon

ding

Abs(streptavidin)

Y-90

Mou

sexeno

graft

mod

el[103]

Colon

cancer

CEA

hBS14(H

SG)

Y-90

Mou

sexeno

graft

mod

el[96]

MN14

(MORF

)Re

-188

Mou

sexeno

graft

mod

el[98]

Ep-C

AM

NR-LU

-10(H

SG)

Y-90

Hum

an(phase

II)

[87]

Gastro

intestinalcancer

TAG-72

CC49-(scFv) 4(stre

ptavidin)

Y-90

Hum

an(phase

I)[104]

Glio

ma

Tenascin

BC4(biotin

)Y-90

Hum

an(phase

II)

[105]


and tumor uptake is desired Radiolabeled peptides target-ing intended tumor can be available due to the preferablepharmacokinetics and low antigenicity In this approachcontrol of the affinity (specific accumulation) of radiolabeledconjugates to tumor tissue is also important

21 Hematological Cancers It is reported that anticancerresponses occur at relatively low radiation-absorbed doses(ie less than 10Gy) in non-Hodgkin lymphoma (NHL)[31 32] 90Y-ibritumomab tiuxetan (Zevalin) and 131I-tositumomab (Bexxar) are the two FDA-approved radiola-beled anti-CD20 murine Abs that have been administeredto patients with NHL [33 34] However neither treatmentis applied to patients with more than 25 bone marrowinvolvement because these patients might suffer from moresevere hematologic toxicity Several other radiolabeled Abshave been tested in hematological cancers A 131I-labeledanti-CD20 mAb (131I-rituximab) [35ndash37] and an 90Y-labeledanti-CD22mAb (90Y-epratuzumab tetraxetan) [32 38 39] arein advanced clinical trials

Shorter-range radioisotopes (120572-particle emitters) can be abetter option for the treatment of patients with hematologicalcancer In previous investigations RIT using 213Bi-labeledanti-CD33 IgG was performed in myeloid leukemia [40 41]however short physical half-life of 213Bi poses a problemfor conjugate preparation Thus longer-lived emitters suchas 211At or 225Ac which can emit four daughter 120572-particlesduring its decay might be available RITs using Auger-emitters such as iodine-125 (125I) gallium-67 (67Ga) andindium-111 (111In) could be suitable for micrometastaticdisease Potential cytotoxicity of 67Ga-labeled anti-CD74 Abwas observed in a study using Raji B-lymphoma cells [42]

Due to the expression of these targeting antigens normalB cells also have potencies to bind to the radiolabeledAbs Thus at low protein doses the radioimmunoconjugateswould be trapped to spleen rapidly where a considerablenumber of B cells exist To avoid this issue unconjugatedAb issometimes added to the systemwhich blocks the unfavorabledistribution [43ndash45] In addition these Abs can enhance atumor cellrsquos sensitivity to radiation and chemotherapy [46ndash48] and thus therapeutic responses would be achieved by acombination of the unconjugated Ab and targeted radiation

22 Solid Cancers RIT as a treatment protocol could beuseful in the therapy for nonhematological cancers as wellhowever convincing therapeutic outcomes have not beenobtained yet in patients with solid cancer One of the mostobvious issues with RITs in solid cancers is that unlikelymphoma most of the Abs used are unable to affecttumor growth To elicit clinical benefits for patients withadvanced andor disseminated solid cancers several designsof the treatment are being undertaken improvement ofAb uptake and enhancement of radiosensitization of cancercells [49ndash51]

Here some examples of RITs targeting solid cancer areshown

221 Colorectal Cancer Owing to the early characterizationand ubiquitous expression in colorectal cancer carcinoem-bryonic antigen (CEA) [52] has been the most commontarget for RIT in this disease cT8466 a chimeric IgG againstthe A3 epitope of CEA possesses highly selective affinity tocancer cells expressing CEA [53] RIT using 90Y-cT8466 wasperformed by Wong et al [54 55] with minor responses intumor regression Several other murine anti-CEA RIT agentshave been evaluated including 131I-NP-4 F(ab1015840)

2 131I-F6

F(ab1015840)2 131I-A5B7 131I-COL-1 and 186Re-NR-CO-02 F(ab1015840)

2

[50 56ndash60]A33 one of the glycoproteins is expressed homoge-

neously in more than 95 of all colorectal cancers [61]and thus the humanized Ab (huA33) has been developedPreclinical studies using 211At-labeled huA33 indicate that theuptake in tumor was found to be specific to the presence ofA33 antigen [62]

In a trial study performed by Liersch et al patients havingundergone liver resection for metastatic colorectal cancerwere treated with 131I-labeled humanized anti-CEACAM5IgG [63]Median survival of patients having received RITwassignificantly longer than that of control subjects [64]

222 Breast CancerOvarian Cancer Trastuzumab is ahumanized IgG mAb directed against the extracellulardomain of the human epidermal growth factor receptor2 (HER-2)neu that is commonly overexpressed in breastovarian and gastrointestinal tumors [65] This Ab has beenlabeled with several radioisotopes such as 90Y [66] and 111In[67] for clinical study of breast cancer Phase I study ofintraperitoneal 212Pb-trastuzumab for patientswith advancedovarian cancer is also ongoing [68]

MUC-1 a mucin epitope is commonly expressed on thesurface of breast cancer cells Schrier et al reported on aphase I study using the murine Ab labeled with 90Y (90Y-MX-DTPA-BrE-3) and autologous stemcell rescue in patientswith breast cancer [69] One-half of the patients exhibitedobjective partial response to the therapy To overcome thelimitation of repeated dosing an 90Y-labeled humanized Abhas also been evaluated for use with stem cell support [70]

Cell-surface sodium-dependent phosphate transportprotein 2b which is highly expressed on ovarian cancercells is recognized by the murine IgG MX35 [71 72] Thepotential usefulness of this Ab has been established inpreclinical models and then intraperitoneal administrationof 211At-MX35 F(ab1015840)

2was undertaken to a phase I

trial to determine the pharmacokinetics dosimetry andtoxicity [73]

223 Prostate Cancer MUC-1 described above for its usein breast cancer has also been shown to be upregulatedin androgen-independent prostate cancer cells making it agood target for RIT [74] m170 a murine mAb was labeledwith 90Y which was examined in patients with metastatic


androgen-independent prostate cancer [75] Many patientswho complain of pain at the entry of study reported a signif-icant reduction in pain following therapy A phase I study of90Y-2IT-BAD-m170 combined with low-dose paclitaxel wasalso performed by the same group [76]

J591 is an IgG mAb against the extracellular domain ofprostate-specific membrane antigen (PSMA) Several J591constructs labeled with 90Y [77] 177Lu [78] and 213Bi [79]have also been evaluated in patients with prostate cancer

3 Indirect Method

In ldquoindirect methodrdquo directly radiolabeled mAbs are notused that is mAbs and radioactive effector molecules areadministered separately and they will be conjugated in vivoThis technique can improve target to nontarget ratio toachieve high imaging contrast andor therapeutic efficacyIn a field of RIT this strategy is referred to as pretargetedradioimmunotherapy (PRIT) and was developed to avoidthe issues associated with the prolonged residence times ofradiolabeled Ab in 1980s [80 81]

PRIT is a technique that enables the Ab localization phaseto be temporally separated from the radioisotope administra-tion in the form of a small molecular hapten This approachinvolves the sequential administration of (1) a bispecific mAbderivative (bs-mAb) capable of binding a tumor antigen and achelate and (2) a small molecular weight radiolabeled effectorspecies The radiolabeled species is administered followinga scheduled lag period to allow the bs-mAbs to accumulateto the target site and any residual bs-mAbs are cleared fromthe circulation The bs-mAb is not radiolabeled directlyand thus no exposure would occur during ldquounlabeledrdquo bs-mAbs localize to the tumor by themselves In some casesan additional ldquoclearing moleculerdquo which removes unboundbs-mAb from the circulation is administered prior to theradiolabeled effector Consequently improvement of tumorto background ratios has been achieved [82 83] Summarizedscheme is shown in Figure 1

A key to successful implementation of the pretargetingmethod consists of the high target specificity and affinityoffered by bs-mAb and the superior pharmacokinetic char-acteristics of a low molecular weight compound The smallsize and inert properties of the radiolabeled effector allowit to distribute easily in the fluidic volume and then to beeliminated rapidly thereby decreasing the overall radiationburden to nontarget organs and tissues such as bone marrow[84] Also PRIT increases the dose rate to the cancer ascompared with a RIT by using directly radiolabeled IgG thattakes 1-2 days to reach maximum distribution

To ensure the two parts (bs-mAb and radiolabeled effec-tor) bind to each other strongly upon interaction at cancerousregion each must be suitably modified with complementaryreactive species One of the approaches is based on avidinor streptavidin in conjunction with biotin in a variety ofconfigurations [85] Avidins could bind as many as fourbiotin molecules with very high binding constant (10minus15M)and thus some avidinbiotin-based PRIT were examinedclinically [86ndash88] In this protocol clearing agentwas injected

to remove residual streptavidinated Abs from the blood Theprimary issue with PRIT depending on avidin (streptavidin)is the immunogenicity of these foreign proteins [89 90]

Conjugation of radioisotopes to bs-mAb is controlled byanother constituent The approach has been utilized witha bs-mAb to histamine-succinyl-glycine (HSG) [91 92] Byjoining two haptens via a short peptide uptake and retentionof the radiolabeled effector (divalent hapten-peptide) wouldbe enhanced locally within the cancer compared with thoseof the monovalent form [93ndash95] Di-HSG-peptide struc-tures have been developed for binding several radioisotopesincluding 90Y and 99mTc [96 97] Other methods employcomplementary synthetic low immunogenic DNA analogsmorpholinos as bridging agents [98 99]

31 PRIT for Hematological Cancers In preclinical studiespretargeting method showed better responses with muchless hematologic toxicity and thus represents a significantimprovement over the RIA using anti-CD20 IgG agentsradiolabeled directly [100]

Among the hematological cancers NHL therapy hasbeen examined in detail by pretargeting In conventionalNHL model mice PRIT with a tri-Fab fragment followedby 90Y-labeled effector led to dramatic cure rates comparedto RIT with direct 90Y-veltuzumab which is a radiolabeledanti-CD20 Ab [101] Similar therapeutic responses werealso achieved using the streptavidin-biotin format of PRITin the Ramos lymphoma model using a combination ofanti-CD20 Ab-streptavidin fusion protein 1F5(scFv)

4SA and

90Y-DOTA-biotin [102] Pagel et al compared therapeuticefficacy between direct RIT and PRIT in xenograft models oflymphoma using CD20 CD22 and MHC class II cell surfacereceptor (HLA-DR) as the targets In this study PRIT by thestreptavidin-biotin conjugation showed higher therapeuticindices and superior tumor regression [103]

32 PRIT for Solid Cancers A phase II trial was exam-ined with 90Y-DOTA-biotin pretargeted with a NR-LU-10an anti-Ep-CAM (epithelial glycoprotein-2) IgG-streptavidinconjugate in advanced colorectal cancer [87] however nosignificant responses were observed More recently a recom-binant protein of streptavidin with four CC49 (anti-tumor-associated glycoprotein 72 anti-TAG-72) single chains and90Y-labeled biotin pair has been tested in patients withgastrointestinal malignancy [104]

In a field of brain tumor patients with grade III gliomaand glioblastoma were pretargeted with 90Y-labeled biotinresulting in a significant extension of survival in the PRITsubjects [105]

4 Concluding Remarks

Because Ab-based targeted radiation is considered tomediatedirect cytotoxic effects RIT (PRIT) could provide us withopportunities for safer and more efficient cancer treatmentIndeed these techniques have been extensively used asconventional anticancer strategies Especially RIT (PRIT)has been effective in hematological cancers There are also


Blood vessel

Step 1 Step 2

(Clearing agent)

Time

Tumor tissue

Tumor cell

Slow clearance Rapid clearance

Cell death

Figure 1 Schematic diagram of pretargeting approach

developments of new immunostimulant for lymphoma thatis combined with RIT (PRIT) which can enhance the overalltherapeutic response

On the contrary responses to RIT (PRIT) are generallylow in solid cancer and it might be due to the unconventionalmicroenvironments Oxygen concentrations less than 002decrease the vulnerability of cancer cells to ionizing radiation[106] and even milder hypoxia produces a substantial levelof resistance to irradiation [107] Strategies to radiosensitizethe lesions by means of an increased supply of oxygen ortreatment of nitroimidazole analog [108] would help enhancethe efficacy of RIT (PRIT)

RIT (PRIT) is a valuable treatment modality which candetect and quantify the accumulation of therapeutic agentsreadily Thus molecular imaging approach can be adaptedto select patients to decide the treatment strategy and toassess the therapeutic benefit Developments of novel Ab-based targeted therapeutics and the combination with otherinterventions should support cancer therapy in future

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper

References

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[2] D Pressman and L Korngold ldquoThe in vivo localization of anti-Wagner-osteogenic-sarcoma antibodiesrdquo Cancer vol 6 no 3pp 619ndash623 1953

[3] R W Wissler P A Barker M H Flax et al ldquoA study of thepreparation localization and effects of antitumor antibodieslabeled with I131rdquo Cancer Research vol 16 no 8 pp 761ndash7731956

[4] O A Gansow M W Brechbiel S Mirzadeh D Colcher andM Roselli ldquoChelates and antibodies current methods and newdirectionsrdquo Cancer Treatment and Research vol 51 pp 153ndash1711990

[5] M K Moi S J DeNardo and C F Meares ldquoStable bifunctionalchelates of metals used in radiotherapyrdquo Cancer Research vol50 no 3 pp S789ndashS793 1990

[6] DM Goldenberg and RM Sharkey ldquoAdvances in cancer ther-apy with radiolabeled monoclonal antibodiesrdquo The QuarterlyJournal of Nuclear Medicine and Molecular Imaging vol 50 no4 pp 248ndash264 2006

[7] K M Prise and J M OSullivan ldquoRadiation-induced bystandersignalling in cancer therapyrdquo Nature Reviews Cancer vol 9 no5 pp 351ndash360 2009

[8] J A Bertout S A Patel and M C Simon ldquoThe impact of O2

availability on human cancerrdquoNature Reviews Cancer vol 8 no12 pp 967ndash975 2008

[9] P Vaupel and A Mayer ldquoHypoxia in cancer significance andimpact on clinical outcomerdquo Cancer and Metastasis Reviewsvol 26 no 2 pp 225ndash239 2007

[10] G Kroemer L Galluzzi and C Brenner ldquoMitochondrial mem-brane permeabilization in cell deathrdquo Physiological Reviews vol87 no 1 pp 99ndash163 2007

[11] L Cabon P Galan-Malo A Bouharrour et al ldquoBID regulatesAIF-mediated caspase-independent necroptosis by promotingBAX activationrdquo Cell Death and Differentiation vol 19 no 2pp 245ndash256 2012

[12] R Ganss E Ryschich E Klar B Arnold andG J HammerlingldquoCombination of T-cell therapy and trigger of inflammationinduces remodeling of the vasculature and tumor eradicationrdquoCancer Research vol 62 no 5 pp 1462ndash1470 2002


[13] E Tartour H Pere B Maillere et al ldquoAngiogenesis andimmunity a bidirectional link potentially relevant for themonitoring of antiangiogenic therapy and the development ofnovel therapeutic combination with immunotherapyrdquo Cancerand Metastasis Reviews vol 30 no 1 pp 83ndash95 2011

[14] RWHowell ldquoAuger processes in the 21st centuryrdquo InternationalJournal of Radiation Biology vol 84 no 12 pp 959ndash975 2008

[15] M J Mattes ldquoRadionuclide-antibody conjugates for single-cellcytotoxicityrdquo Cancer vol 94 no 4 pp 1215ndash1223 2002

[16] G LOng S E ElsamraDMGoldenberg andM JulesMattesldquoSingle-cell cytotoxicity with radiolabeled antibodiesrdquo ClinicalCancer Research vol 7 no 1 pp 192ndash201 2001

[17] A K Claesson B Stenerlow L Jacobsson and K ElmrothldquoRelative biological effectiveness of the 120572-particle emitter 211Atfor double-strand break induction in human fibroblastsrdquo Radi-ation Research vol 167 no 3 pp 312ndash318 2007

[18] E J Hall and A J Giaccia Radiology for the RadiologistLippincott Williams amp Wilkins Philadelphia Pa USA 7thedition 2007

[19] M R McDevitt G Sgouros R D Finn et al ldquoRadioim-munotherapy with 120572-emitting nuclidesrdquo European Journal ofNuclear Medicine vol 25 no 9 pp 1341ndash1351 1998

[20] MCherel S Gouard J Gaschet et al ldquo 213Bi radioimmunother-apy with an anti-mCD138 monoclonal antibody in a murinemodel of multiple myelomardquo The Journal of Nuclear Medicinevol 54 no 9 pp 1597ndash1604 2013

[21] G Vaidyanathan and M R Zalutsky ldquoAstatine radiopharma-ceuticals prospects and problemsrdquo Current Radiopharmaceuti-cals vol 1 no 3 pp 177ndash196 2008

[22] M Miederer D A Scheinberg and M R McDevitt ldquoRealizingthe potential of the Actinium-225 radionuclide generator intargeted alpha particle therapy applicationsrdquo Advanced DrugDelivery Reviews vol 60 no 12 pp 1371ndash1382 2008

[23] M L Sautter-Bihl G Herbold and H Bihl ldquoMinimalresidual disease a target for radioimmunotherapy with 131I-labeled monoclonal antibodies Some dosimetric considera-tionsrdquo Recent Results in Cancer Research vol 141 pp 67ndash751996

[24] K Chen and X Chen ldquoDesign and development of molecularimaging probesrdquo Current Topics in Medicinal Chemistry vol 10no 12 pp 1227ndash1236 2010

[25] K Chen and P S Conti ldquoTarget-specific delivery of peptide-based probes for PET imagingrdquo Advanced Drug DeliveryReviews vol 62 no 11 pp 1005ndash1022 2010

[26] G Kohler and C Milstein ldquoContinuous cultures of fused cellssecreting antibody of predefined specificityrdquo Nature vol 256no 5517 pp 495ndash497 1975

[27] J L Murray M G Rosenblum L Lamki et al ldquoClinicalparameters related to optimal tumor localization of indium-111-labeled mouse antimelanoma monoclonal antibody ZME-018rdquoThe Journal of Nuclear Medicine vol 28 no 1 pp 25ndash33 1987

[28] S F Rosebrough Z D Grossman J G McAfee et alldquoThrombus imaging with Indium-111 and Iodine-131-labeledfibrin-specific monoclonal antibody and its F(abrsquo)

2and Fab

fragmentsrdquo The Journal of Nuclear Medicine vol 29 no 7 pp1212ndash1222 1988

[29] A M Wu and P D Senter ldquoArming antibodies prospects andchallenges for immunoconjugatesrdquo Nature Biotechnology vol23 no 9 pp 1137ndash1146 2005

[30] L A Maleki B Baradaran and J Majidi ldquoFuture prospectsof monoclonal antibodies as magic bullets in immunotherapyrdquoHuman Antibodies vol 22 no 1-2 pp 9ndash13 2013

[31] G Sgouros S Squeri A M Ballangrud et al ldquoPatient-specific3-dimensional dosimetry in non-Hodgkinrsquos lymphoma patientstreated with 131I-anti-B1 antibody assessment of tumor dose-responserdquo The Journal of Nuclear Medicine vol 44 no 2 pp260ndash268 2003

[32] R M Sharkey A Brenner J Burton et al ldquoRadioimmunother-apy of non-Hodgkinrsquos lymphoma with 90Y-DOTA humanizedanti-CD22 IgG (90Y-Epratuzumab) do tumor targeting anddosimetry predict therapeutic responserdquoThe Journal of NuclearMedicine vol 44 no 12 pp 2000ndash2018 2003

[33] S J Goldsmith ldquoRadioimmunotherapy of lymphoma bexxarand zevalinrdquo Seminars in Nuclear Medicine vol 40 no 2 pp122ndash135 2010

[34] M S Kaminski M Tuck J Estes et al ldquo 131I-tositumomabtherapy as initial treatment for follicular lymphomardquo The NewEngland Journal of Medicine vol 352 no 5 pp 441ndash449 2005

[35] M F Leahy and J H Turner ldquoRadioimmunotherapy of relapsedindolent non-Hodgkin lymphoma with 131I-rituximab in rou-tine clinical practice 10-year single-institution experience of142 consecutive patientsrdquo Blood vol 117 no 1 pp 45ndash52 2011

[36] J H Turner A A Martindale J Boucek P G Claringboldand M F Leahy ldquo 131I-anti CD20 radioimmunotherapy ofrelapsed or refractory non-Hodgkins lymphoma a phase IIclinical trial of a nonmyeloablative dose regimen of chimericrituximab radiolabeled in a hospitalrdquo Cancer Biotherapy ampRadiopharmaceuticals vol 18 no 4 pp 513ndash524 2003

[37] T M Illidge M Bayne N S Brown et al ldquoPhase 12 studyof fractionated 131I-rituximab in low-grade B-cell lymphomathe effect of prior rituximab dosing and tumor burden onsubsequent radioimmunotherapyrdquo Blood vol 113 no 7 pp1412ndash1421 2009

[38] F Morschhauser F Kraeber-Bodere W A Wegener et alldquoHigh rates of durable responses with anti-CD22 fractionatedradioimmunotherapy results of a multicenter phase III studyin non-Hodgkinrsquos lymphomardquo Journal of Clinical Oncology vol28 no 23 pp 3709ndash3716 2010

[39] G L Griffiths S V Govindan R M Sharkey D R Fisher andD M Goldenberg ldquo 90Y-DOTA-hLL2 an agent for radioim-munotherapy of non-Hodgkinrsquos lymphomardquo The Journal ofNuclear Medicine vol 44 no 1 pp 77ndash84 2003

[40] G Sgouros A M Ballangrud J G Jurcic et al ldquoPharmacoki-netics and dosimetry of an 120572-particle emitter labeled antibody213Bi-HuM195 (anti-CD33) in patients with leukemiardquo TheJournal of Nuclear Medicine vol 40 no 11 pp 1935ndash1946 1999

[41] J G Jurcic S M Larson G Sgouros et al ldquoTargeted 120572 particleimmunotherapy for myeloid leukemiardquo Blood vol 100 no 4pp 1233ndash1239 2002

[42] R B Michel M W Brechbiel and M J Mattes ldquoA comparisonof 4 radionuclides conjugated to antibodies for single-cell killrdquoThe Journal of Nuclear Medicine vol 44 no 4 pp 632ndash6402003

[43] M S Kaminski K R Zasadny I R Francis et al ldquoIodine-131-anti-B1 radioimmunotherapy for B-cell lymphomardquo Journal ofClinical Oncology vol 14 no 7 pp 1974ndash1981 1996

[44] P McLaughlin A J Grillo-Lopez B K Link et al ldquoRituximabchimeric anti-CD20 monoclonal antibody therapy for relapsedindolent lymphoma half of patients respond to a four-dosetreatment programrdquo Journal of Clinical Oncology vol 16 no 8pp 2825ndash2833 1998

[45] T E Witzig C A White G A Wiseman et al ldquoPhase III trialof IDEC-Y2B8 radioimmunotherapy for treatment of relapsed


or refractory CD20+ B-cell non-Hodgkinrsquos lymphomardquo Journalof Clinical Oncology vol 17 no 12 pp 3793ndash3803 1999

[46] Y Du J Honeychurch M S Cragg et al ldquoAntibody-inducedintracellular signaling works in combination with radiation toeradicate lymphoma in radioimmunotherapyrdquo Blood vol 103no 4 pp 1485ndash1494 2004

[47] N S Kapadia J M Engles and R L Wahl ldquoIn vitro evaluationof radioprotective and radiosensitizing effects of rituximabrdquoTheJournal of Nuclear Medicine vol 49 no 4 pp 674ndash678 2008

[48] A Ivanov S Krysov M S Cragg and T Illidge ldquoRadiationtherapy with tositumomab (B1) anti-CD20 monoclonal anti-body initiates extracellular signal-regulated kinasemitogen-activated protein kinase-dependent cell death that overcomesresistance to apoptosisrdquo Clinical Cancer Research vol 14 no 15pp 4925ndash4934 2008

[49] R F Meredith M B Khazaeli W E Plott et al ldquoPhase IIstudy of dual 131I-labeled monoclonal antibody therapy withinterferon in patients withmetastatic colorectal cancerrdquoClinicalCancer Research vol 2 no 11 pp 1811ndash1818 1996

[50] T Meyer A M Gaya G Dancey et al ldquoA phase I trialof radioimmunotherapy with 131I-A5B7 anti-CEA antibody incombination with combretastatin-A4-phosphate in advancedgastrointestinal carcinomasrdquo Clinical Cancer Research vol 15no 13 pp 4484ndash4492 2009

[51] F Kraeber-Bodere C Bodet-Milin C Niaudet et al ldquoCom-parative toxicity and efficacy of combined radioimmunother-apy and antiangiogenic therapy in carcinoembryonic antigen-expressing medullary thyroid cancer xenograftrdquo The Journal ofNuclear Medicine vol 51 no 4 pp 624ndash631 2010

[52] P Gold and S O Freedman ldquoDemonstration of tumor-specificantigens in human colonic carcinomata by immunological tol-erance and absorption techniquesrdquoThe Journal of ExperimentalMedicine vol 121 pp 439ndash462 1965

[53] J D Beatty R B Duda L E Williams et al ldquoPreoperativeimaging of colorectal carcinoma with 111In-labeled anticarci-noembryonic antigen monoclonal antibodyrdquo Cancer Researchvol 46 no 12 pp 6494ndash6502 1986

[54] J Y C Wong S Shibata L E Williams et al ldquoA phase I trialof 90Y-anticarcinoembryonic antigen chimeric T8466 radioim-munotherapy with 5-fluorouracil in patients with metastaticcolorectal cancerrdquo Clinical Cancer Research vol 9 no 16 pp5842ndash5852 2003

[55] J Y C Wong D Z Chu L E Williams et al ldquoA phase I trialof 90Y-DOTA-anti-CEA chimeric T8466 (cT8466) radioim-munotherapy in patients with metastatic CEA-producingmalignanciesrdquo Cancer Biotherapy and Radiopharmaceuticalsvol 21 no 2 pp 88ndash100 2006

[56] T M Behr R M Sharkey M E Juweid et al ldquoPhase IIIclinical radioimmunotherapy with an iodine-131-labeled anti-carcinoembryonic antigen murine monoclonal antibody IgGrdquoThe Journal of NuclearMedicine vol 38 no 6 pp 858ndash870 1997

[57] M E Juweid R M Sharkey T Behr et al ldquoRadioimmunother-apy of patients with small-volume tumors using iodine-131-labeled anti-CEA monoclonal antibody NP-4 F(ab1015840)

2rdquo The

Journal of Nuclear Medicine vol 37 no 9 pp 1504ndash1510 1996[58] M Ychou D Azria C Menkarios et al ldquoAdjuvant

radioimmunotherapy trial with iodine-131-labeled anti-carcinoembryonic antigen monoclonal antibody F6 F(ab1015840)

2

after resection of liver metastases from colorectal cancerrdquoClinical Cancer Research vol 14 no 11 pp 3487ndash3493 2008

[59] B Yu J Carrasquillo D Milenic et al ldquoPhase I trial of iodine131-labeled COL-1 in patients with gastrointestinal malignan-cies influence of serum carcinoembryonic antigen and tumorbulk on pharmacokineticsrdquo Journal of Clinical Oncology vol 14no 6 pp 1798ndash1809 1996

[60] H B Breitz P L Weiden J-L Vanderheyden et al ldquoClinicalexperience with rhenium-186-labeled monoclonal antibodiesfor radioimmunotherapy results of Phase I trialsrdquo The Journalof Nuclear Medicine vol 33 no 6 pp 1099ndash1112 1992

[61] P Garin-Chesa J Sakamoto S Welt F X Real W J Rettigand L J Old ldquoOrgan-specific expression of the colon cancerantigen A33 a cell surface target for antibody-based therapyrdquoInternational Journal of Oncology vol 9 no 3 pp 465ndash4711996

[62] Y Almqvist A C Steffen H Lundqvist H Jensen VTolmachev and A Sundin ldquoBiodistribution of 211At-labeledhumanized monoclonal antibody A33rdquo Cancer Biotherapy andRadiopharmaceuticals vol 22 no 4 pp 480ndash487 2007

[63] T Liersch J Meller B Kulle et al ldquoPhase II trial of carcinoem-bryonic antigen radioimmunotherapy with 131I-labetuzumabafter salvage resection of colorectal metastases in the liver five-year safety and efficacy resultsrdquo Journal of Clinical Oncology vol23 no 27 pp 6763ndash6770 2005

[64] T Liersch J Meller M Bittrich B Kulle H Becker and DMGoldenberg ldquoUpdate of carcinoembryonic antigen radioim-munotherapy with 131I-labetuzumab after salvage resectionof colorectal liver metastases comparison of outcome to acontemporaneous control grouprdquo Annals of Surgical Oncologyvol 14 no 9 pp 2577ndash2590 2007

[65] P Carter L Presta C M Gorman et al ldquoHumanizationof an anti-p185HER2 antibody for human cancer therapyrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 89 no 10 pp 4285ndash4289 1992

[66] D M Crow L Williams D Colcher J Y C Wong ARaubitschek and J E Shively ldquoCombined radioimmunother-apy and chemotherapy of breast tumors with Y-90-labeledanti-Her2 and anti-CEA antibodies with taxolrdquo BioconjugateChemistry vol 16 no 5 pp 1117ndash1125 2005

[67] D L Costantini K Bateman K McLarty K A Vallis andR M Reilly ldquoTrastuzumab-resistant breast cancer cells remainsensitive to the Auger electron-emitting radiotherapeutic agent111In-NLS-trastuzumab and are radiosensitized by methotrex-aterdquo The Journal of Nuclear Medicine vol 49 no 9 pp 1498ndash1505 2008

[68] R F Meredith ldquoSafety study of 212Pb-TCMC-trastuzumabradio immunotherapyrdquo httpclinicaltrialsgovct2showNCT-01384253

[69] D M Schrier S M Stemmer T Johnson et al ldquoHigh-dose90YMx-diethylenetriaminepentaacetic acid (DTPA)-BrE-3 andautologous hematopoietic stem cell support (AHSCS) for thetreatment of advanced breast cancer a phase I trialrdquo CancerResearch vol 55 no 23 pp 5921sndash5924s 1995

[70] P J Cagnoni R L Ceriani W C Cole et al ldquoPhase Istudy of high-dose radioimmunotherapy with 90-Y-hu-BrE-3followed by autologous stem cell support (ASCS) in patientswith metastatic breast cancerrdquo Cancer Biotherapy amp Radiophar-maceuticals vol 13 no 4 p 328 1998

[71] M Welshinger B W T Yin and K O Lloyd ldquoInitial immuno-chemical characterization of MX35 ovarian cancer antigenrdquoGynecologic Oncology vol 67 no 2 pp 188ndash192 1997


[72] BW T Yin R Kiyamova R Chua et al ldquoMonoclonal antibodyMX35 detects the membrane transporter NaPi2b (SLC34A2) inhuman carcinomasrdquo Cancer Immunity vol 8 article 3 2008

[73] H Andersson E Cederkrantz T Back et al ldquoIntraperitoneal120572-particle radioimmunotherapy of ovarian cancer patientspharmacokinetics and dosimetry of 211At-MX35 F(ab1015840)

2 A

Phase I Studyrdquo The Journal of Nuclear Medicine vol 50 no 7pp 1153ndash1160 2009

[74] S J DeNardo CM Richman H Albrecht et al ldquoEnhancementof the therapeutic index from nonmyeloablative and myeloab-lative toward pretargeted radioimmunotherapy for metastaticprostate cancerrdquo Clinical Cancer Research vol 11 no 19 pp7187sndash7194s 2005

[75] R T OrsquoDonnell S J DeNardo A Yuan et al ldquoRadioim-munotherapy with 111In90Y-2IT-BAD-m170 for metastaticprostate cancerrdquo Clinical Cancer Research vol 7 no 6 pp 1561ndash1568 2001

[76] CMRichman S J DeNardo R TOrsquoDonnell et al ldquoHigh-doseradioimmunotherapy combined with fixed low-dose paclitaxelin metastatic prostate and breast cancer by using a MUC-1monoclonal antibody m170 linked to indium-111yttrium-90via a cathepsin cleavable linker with cyclosporine to preventhuman anti-mouse antibodyrdquo Clinical Cancer Research vol 11no 16 pp 5920ndash5927 2005

[77] M I Milowsky D M Nanus L Kostakoglu S VallabhajosulaS J Goldsmith and N H Bander ldquoPhase I trial of yttrium-90-labeled anti-prostate-specific membrane antigen monoclonalantibody J591 for androgen-independent prostate cancerrdquo Jour-nal of Clinical Oncology vol 22 no 13 pp 2522ndash2531 2004

[78] N H Bander M I Milowsky D M Nanus L KostakogluS Vallabhajosula and S J Goldsmith ldquoPhase I trial of177Lutetium-labeled J591 a monoclonal antibody to prostate-specific membrane antigen in patients with androgen-independent prostate cancerrdquo Journal of Clinical Oncology vol23 no 21 pp 4591ndash4601 2005

[79] M R McDevitt E Barendswaard D Ma et al ldquoAn 120572-particleemitting antibody ([213Bi]J591) for radioimmunotherapy ofprostate cancerrdquoCancer Research vol 60 no 21 pp 6095ndash61002000

[80] D T Reardan C F Meares D A Goodwin et al ldquoAntibodiesagainst metal chelatesrdquo Nature vol 316 no 6025 pp 265ndash2681985

[81] D A Goodwin C F Mears M McTigue and G S DavidldquoMonoclonal antibody hapten radiopharmaceutical deliveryrdquoNuclear Medicine Communications vol 7 no 8 pp 569ndash5801986

[82] D A Goodwin C F Meares M J McCall M McTigueand W Chaovapong ldquoPre-targeted immunoscintigraphy ofmurine tumors with indium-111-labeled bifunctional haptensrdquoThe Journal of NuclearMedicine vol 29 no 2 pp 226ndash234 1988

[83] D M Goldenberg R M Sharkey G Paganelli J Barbet andJ Chatal ldquoAntibody pretargeting advances cancer radioim-munodetection and radioimmunotherapyrdquo Journal of ClinicalOncology vol 24 no 5 pp 823ndash834 2006

[84] B M Zeglis K K Sevak T Reiner et al ldquoA pretargetedPET imaging strategy based on bioorthogonal diels-alder clickchemistryrdquo The Journal of Nuclear Medicine vol 54 no 8 pp1389ndash1396 2013

[85] D J Hnatowich F Virzi and M Rusckowski ldquoInvestigationsof avidin and biotin for imaging applicationsrdquo The Journal ofNuclear Medicine vol 28 no 8 pp 1294ndash1302 1987

[86] H B Breitz P L Weiden P L Beaumier et al ldquoClinical opti-mization of pretargeted radioimmunotherapy with antibody-streptavidin conjugate and 90Y-DOTA-biotinrdquo The Journal ofNuclear Medicine vol 41 no 1 pp 131ndash140 2000

[87] S J Knox M L Goris M Tempero et al ldquoPhase II trialof yttrium-90-DOTA-biotin pretargeted by NR-LU-10 anti-bodystreptavidin in patients with metastatic colon cancerrdquoClinical Cancer Research vol 6 no 2 pp 406ndash414 2000

[88] J Schultz Y Lin J Sanderson et al ldquoA tetravalent single-chainantibody-streptavidin fusion protein for pretargeted lymphomatherapyrdquo Cancer Research vol 60 no 23 pp 6663ndash6669 2000

[89] G Paganelli and M Chinol ldquoRadioimmunotherapy is avidin-biotin pretargeting the preferred choice among pretargetingmethodsrdquo European Journal of NuclearMedicine andMolecularImaging vol 30 no 5 pp 773ndash776 2003

[90] DM Goldenberg C H Chang RM Sharkey et al ldquoRadioim-munotherapy is avidin-biotin pretargeting the preferred choiceamong pretargeting methodsrdquo European Journal of NuclearMedicine and Molecular Imaging vol 30 no 5 pp 777ndash7802003

[91] E Janevik-Ivanovska E Gautherot M Hillairet de Boisferon etal ldquoBivalent hapten-bearing peptides designed for iodine-131pretargeted radioimmunotherapyrdquo Bioconjugate Chemistry vol8 no 4 pp 526ndash533 1997

[92] E A Rossi D M Goldenberg T M Cardillo W J McBrideR M Sharkey and C Chang ldquoStably tethered multifunctionalstructures of defined composition made by the dock and lockmethod for use in cancer targetingrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 103 no18 pp 6841ndash6846 2006

[93] J-M le Doussal M Martin E Gautherot M Delaage and JBarbet ldquoIn vitro and in vivo targeting of radiolabeled mono-valent and divalent haptens with dual specificity monoclonalantibody conjugates enhanced divalent hapten affinity for cell-bound antibody conjugaterdquo The Journal of Nuclear Medicinevol 30 no 8 pp 1358ndash1366 1989

[94] D A Goodwin C F Meares M McTigue et al ldquoPretargetedimmunoscintigraphy effect of hapten valency onmurine tumoruptakerdquo The Journal of Nuclear Medicine vol 33 no 11 pp2006ndash2013 1992

[95] O C Boerman M H G C Kranenborg E Oosterwijk et alldquoPretargeting of renal cell carcinoma improved tumor targetingwith a bivalent chelaterdquo Cancer Research vol 59 no 17 pp4400ndash4405 1999

[96] H Karacay P Brard R M Sharkey et al ldquoTherapeutic advan-tage of pretargeted radioimmunotherapy using a recombinantbispecific antibody in a human colon cancer xenograftrdquoClinicalCancer Research vol 11 no 21 pp 7879ndash7885 2005

[97] R M Sharkey T M Cardillo E A Rossi et al ldquoSignal ampli-fication in molecular imaging by pretargeting a multivalentbispecific antibodyrdquo Nature Medicine vol 11 no 11 pp 1250ndash1255 2005

[98] G Liu S Dou G Mardirossian et al ldquoSuccessful radiotherapyof tumor in pretargeted mice by 188Re-radiolabeled phospho-rodiamidate morpholino oligomer a synthetic DNA analoguerdquoClinical Cancer Research vol 12 no 16 pp 4958ndash4964 2006

[99] G Liu S Dou P H Pretorius X Liu M Rusckowski and D JHnatowich ldquoPretargeting CWR22 prostate tumor in mice withMORF-B723 antibody and radiolabeled cMORFrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 35 no2 pp 272ndash280 2008


[100] R M Sharkey H Karacay C R Johnson et al ldquoPretargetedversus directly targeted radioimmunotherapy combined withanti-CD20 antibody consolidation therapy of non-HodgkinlymphomardquoThe Journal of Nuclear Medicine vol 50 no 3 pp444ndash453 2009

[101] R M Sharkey H Karacay S Litwin et al ldquoImproved ther-apeutic results by pretargeted radioimmunotherapy of non-Hodgkinrsquos lymphoma with a new recombinant trivalent anti-CD20 bispecific antibodyrdquo Cancer Research vol 68 no 13 pp5282ndash5290 2008

[102] D J Green J M Pagel A Pantelias et al ldquoPretargetedradioimmunotherapy for B-cell lymphomasrdquo Clinical CancerResearch vol 13 no 18 pp 5598sndash5603s 2007

[103] J M Pagel N Orgun D K Hamlin et al ldquoA comparativeanalysis of conventional and pretargeted radioimmunotherapyof B-cell lymphomas by targeting CD20 CD22 and HLA-DRsingly and in combinationsrdquo Blood vol 113 no 20 pp 4903ndash4913 2009

[104] S Shen A Forero A F LoBuglio et al ldquoPatient-specificdosimetry of pretargeted radioimmunotherapy using CC49fusion protein in patients with gastrointestinal malignanciesrdquoThe Journal of Nuclear Medicine vol 46 no 4 pp 642ndash6512005

[105] C Grana M Chinol C Robertson et al ldquoPretargeted adju-vant radioimmunotherapywithYttrium-90-biotin inmalignantglioma patients a pilot studyrdquo British Journal of Cancer vol 86no 2 pp 207ndash212 2002

[106] B G Wouters and L D Skarsgard ldquoLow-dose radiation sensi-tivity and induced radioresistance to cell killing in HT-29 cellsis distinct from the rsquoadaptive responsersquo and cannot be explainedby a subpopulation of sensitive cellsrdquo Radiation Research vol148 no 5 pp 435ndash442 1997

[107] O Tredan C M Galmarini K Patel and I F Tannock ldquoDrugresistance and the solid tumor microenvironmentrdquo Journal ofthe National Cancer Institute vol 99 no 19 pp 1441ndash1454 2007

[108] J Overgaard H S Hansen M Overgaard et al ldquoA randomizeddouble-blind phase III study of nimorazole as a hypoxicradiosensitizer of primary radiotherapy in supraglottic larynxand pharynx carcinoma Results of the Danish Head and NeckCancer Study (DAHANCA) Protocol 5ndash85rdquo Radiotherapy andOncology vol 46 no 2 pp 135ndash146 1998

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Table 1 Radioisotopes used in RIT

Radioisotope Energymax (MeV) Range Half-life120573-Particle emitter

67Cu 058 21mm 26 d90Y 228 120mm 27 d131I 061 20mm 80 d177Lu 050 15mm 67 d186Re 107 45mm 37 d188Re 212 104mm 169 hr

120572-Particle emitter211At 68 80 120583m 72 hr213Bi 83 84 120583m 46min225Ac 60sim80 60sim90 120583m 100 d

Auger-electron emitter125I 2sim500 nm 605 d

by the physical cross-fire effect This means continuous low-dose irradiation from radiolabeled Abs cause lethal effectson nearby normal cells Moreover it is reported that RITsalso evoke the normalization of tumor vasculature [12]presumably owing to facilitation of immune cell migrationtowards the malignant lesions [13]

For therapy therefore120572- or120573-particle emitters are prefer-able Vehicles coupled with radioisotopes emitting Augerelectrons are also available however they need to be localizedclose to DNA due to the very short range of these radiations[14ndash16] Simultaneous emission of 120574 (X) rays which aresuitable for imaging will help measure pharmacokineticparameters and calculate dosimetry of the radioimmunocon-jugates Table 1 shows radioisotopes commonly used for RIT

Among them relatively well-studied and practicalradioisotopes are the 120573-emitters 131I yttrium-90 (90Y) andlutetium-177 (177Lu) Radioisotope to use is selected byconsideration of those radiophysical properties (energy andhalf-life) as well as the labeling chemistry For example 90Ypossesses a higher 120573-particle 119864max and a shorter half-lifewhen compared with 131I On the other hand metal 90Yshould be conjugated to Ab via chelating agent whereas 131Ican form a carbon-iodine bond directly Lutetium-177 hasradiophysical properties similar to 131I and radiolabelingchemistry similar to 90Y

Investigations of RIT using 120572-particle emitters also havebeen developed Because 120572-particle gives its energy to thesurrounding molecules within a narrow range (lt100120583mequivalent to a few cell diameters) it leads to high lin-ear energy transfer (high LET) within the target and lessbystander effect to nontarget tissues compared to Abs labeledwith 120573-emitters In addition to the high LET which leads tothe high relative biological effectiveness (RBE) [17] recentstudies have shown that cytotoxic efficacy of 120572-particle isindependent of the local oxygen concentration and cellcycle state [18] Bismuth-213 (213Bi) astatine-211 (211At)and actinium-225 (225Ac) are well investigated in 120572-particleRIT [19ndash22]

Compared to external beam radiation therapy one ofthe most potent advantages of RIT is the ability to attacknot only the primary tumor but also lesions systemicallymetastasizing In addition targeted radiotherapy using spe-cific vehicle agents is extremely valuable in cases of (1)residual micrometastatic lesions (2) residual tumor marginsafter surgical resection (3) tumors in the circulating bloodincluding hematologicmalignancy and (4)malignancies thatpresent as free-floating cells [23]

Brief data on current RITs provided in this review paperis summarized in Table 2

2 Direct Method

The success of RIT depends on the selective accumulation ofcytotoxic radioisotopes at affected areas Fundamental prop-erties required for vehicles against a particular biomarkerare (1) high binding affinity to the intended target (2) highspecificity (3) high tumor to background ratio (4) highmetabolic stability and (5) low immunogenicity [24 25]From the viewpoint of those molecular characteristics Abshave been considered as suitable agent for the delivery oftherapeutic radioisotopes Moreover the development ofhybridoma technology in 1975 allowed taking advantage ofmAbs in RIT [26]

ldquoDirect methodrdquo requires direct conjugation of cytotoxicradioisotopes to various antitumormAbs (or their fragments)via an appropriate chelator and the single-step administra-tion to patients Consequently many antigenic determinants(mostly on the cell surface) have been targeted byAbs On theother hand one of the most critical obstacles to achieve highbackground ratio in this application is the slow clearance ofAbs from the blood and nontarget tissues due to their highmolecular weight [27 28] Abs will disappear from plasmavery slowly which encourages higher tumor uptake howevera longer duration is needed to reach the maximum tumor tonormal radioactivity ratio Radiation dose for treating patientincreases time-dependently which results in the exposureof radioactive bone marrow leading to the hematologictoxicity Therefore structural diversification of Abs has beenattempted to improve the pharmacokinetic properties Lowermolecular weight fragments of conventional Abs includingF(ab1015840)

2 Fab or its multivalent conjugate minibody diabody

and single chain variable fragments (scFv) could be utilizedwhich retain the essential antigen binding properties andobtain more rapid clearance rates than intact mAbs Thosesmaller types of constructs can traverse the vascular channelsresulting in a more rapid tumor uptake and a faster bloodclearance than parental Abs [29 30] possessing potenciesto achieve superior tumor to background ratios In generalhowever affinities of small Ab forms to tumor antigen arelower than those of Abs and moreover too fast bloodclearance of peptides yields less time to interact with thetarget Therefore absolute tumor uptake for these constructsis lower than those of Abs Further development of theengineered forms holding both favorable pharmacokinetics


Table2AnticancerR

ITsreportedin

thiscentury

Cancer

Targetmolecule

mAb

Radioisotope

Subject

Reference

Dire

ctmetho

d

Non

-Hod

gkin

lymph

oma

CD20

Ibritum

omab

Y-90

Hum

an(in

clinicalu

se)

[33]

Tositum

omab

I-131

Hum

an(in

clinicalu

se)

[313334]

Rituximab

I-131

Hum

an(phase

II)

[35ndash37]

CD22

Epratuzumab

Y-90

Hum

an(phase

II)

[323839]

Myeloid

leuk

emia

CD33

Lintuzum

abBi-213

Hum

an(phase

II)

[4041]

RajiB-lymph

oma

CD74

L243

Ga-67

Cell

[42]

Colorectalcancer

Carcinoembryonica

ntigen

(CEA

)cT

8466

Y-90

Hum

an(phase

I)[5455]

A33

glycop

rotein

huA33

At-211

Mou

sexeno

graft

mod

el[62]


metastases)

CEA

F6F(ab1015840) 2

I-131

Hum

an(phase

II)

[58]

CEA-

related

celladhesio

nmolecule

Labetuzumab

I-131

Hum

an(phase

II)

[6364

]Gastro

intestinalcancer

CEA

A5B

7I-131

Hum

an(phase

I)[48]

Breastcancer

HER

-2Trastuzumab

Y-90

Mou

sexeno

graft

mod

el[66]

Pb-212

Hum

an(phase

I)[68]

NLS

-trastuzumab

In-111

Cell

[67]

Ovaria

ncancer

Na-depend

entp

hosphatetransporter

MX3

5F(ab1015840) 2

At-211

Hum

an(phase

I)[73]

Prostatecancer

MUC-

1m170

Y-90

Hum

an(phase

I)[7576]

J591

Y-90

Hum

an(phase

I)[77]

Lu-177

Hum

an(phase

I)[78]

Bi-213

Mou

sexeno

graft

mod

el[79]

Multip

lemyeloma

CD138

AntiC

D138Ab

Bi-213

Mou

sexeno

graft

mod

el[20]

Indirectmetho

d

Non

-Hod

gkin

lymph

oma

CD20

TF4(H

SG)

Y-90

Mou

sexeno

graft

mod

el[100101]

1F5(scFv) 4(stre

ptavidin)

Y-90

Mou

sexeno

graft

mod

el[102]

CD20C

D22H

LA-D

RCorrespon

ding

Abs(streptavidin)

Y-90

Mou

sexeno

graft

mod

el[103]

Colon

cancer

CEA

hBS14(H

SG)

Y-90

Mou

sexeno

graft

mod

el[96]

MN14

(MORF

)Re

-188

Mou

sexeno

graft

mod

el[98]

Ep-C

AM

NR-LU

-10(H

SG)

Y-90

Hum

an(phase

II)

[87]

Gastro

intestinalcancer

TAG-72

CC49-(scFv) 4(stre

ptavidin)

Y-90

Hum

an(phase

I)[104]

Glio

ma

Tenascin

BC4(biotin

)Y-90

Hum

an(phase

II)

[105]









2 131I-F6


2













3 Indirect Method









4SA and







Blood vessel

Step 1 Step 2

(Clearing agent)

Time

Tumor tissue

Tumor cell


Cell death







References































2and Fab

































2rdquo The



2


















2 A











































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table2AnticancerR

ITsreportedin

thiscentury

Cancer

Targetmolecule

mAb

Radioisotope

Subject

Reference

Dire

ctmetho

d

Non

-Hod

gkin

lymph

oma

CD20

Ibritum

omab

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