Skip to main content

Main menu

  • Home
  • Content
    • Current
    • Ahead of print
    • Past Issues
    • JNM Supplement
    • SNMMI Annual Meeting Abstracts
  • Subscriptions
    • Subscribers
    • Institutional and Non-member
    • Rates
    • Corporate & Special Sales
    • Journal Claims
  • Authors
    • Submit to JNM
    • Information for Authors
    • Assignment of Copyright
    • AQARA requirements
  • Info
    • Permissions
    • Advertisers
    • Continuing Education
  • About
    • About Us
    • Editorial Board
    • Contact Information
  • More
    • Alerts
    • Feedback
    • Help
    • SNMMI Journals
  • SNMMI
    • JNM
    • JNMT
    • SNMMI Journals
    • SNMMI

User menu

  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Journal of Nuclear Medicine
  • SNMMI
    • JNM
    • JNMT
    • SNMMI Journals
    • SNMMI
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Journal of Nuclear Medicine

Advanced Search

  • Home
  • Content
    • Current
    • Ahead of print
    • Past Issues
    • JNM Supplement
    • SNMMI Annual Meeting Abstracts
  • Subscriptions
    • Subscribers
    • Institutional and Non-member
    • Rates
    • Corporate & Special Sales
    • Journal Claims
  • Authors
    • Submit to JNM
    • Information for Authors
    • Assignment of Copyright
    • AQARA requirements
  • Info
    • Permissions
    • Advertisers
    • Continuing Education
  • About
    • About Us
    • Editorial Board
    • Contact Information
  • More
    • Alerts
    • Feedback
    • Help
    • SNMMI Journals
  • Follow JNM on Twitter
  • Visit JNM on Facebook
  • Join JNM on LinkedIn
  • Subscribe to our RSS feeds
OtherContinuing Education

Pretargeted Radioimmunotherapy of Cancer: Progress Step by Step

Otto C. Boerman, Frank G. van Schaijk, Wim J.G. Oyen and Frans H.M. Corstens
Journal of Nuclear Medicine March 2003, 44 (3) 400-411;
Otto C. Boerman
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Frank G. van Schaijk
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Wim J.G. Oyen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Frans H.M. Corstens
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

To enhance the therapeutic efficacy of radioimmunotherapy of cancer, several pretargeting strategies have been developed. In pretargeted radioimmunotherapy, the tumor is pretargeted with an antibody construct that has affinity for the tumor-associated antigen on the one hand and for a radiolabeled hapten on the other. The radiolabeled hapten is administered in a later phase, preferably after the antibody construct has cleared from the circulation. In pretargeted radioimmunotherapy, 2 main approaches can be distinguished: pretargeting strategies based on the avid interaction between streptavidin (SA) or avidin and biotin, and pretargeting strategies based on the use of bispecific antibodies. In pretargeting strategies based on biotin and SA or avidin, the use of a clearing agent that could remove the pretargeting construct from the circulation markedly improved the targeting of the radiolabeled biotin to the tumor. Thus, multistep injection schemes in which 3–5 different agents are subsequently injected were developed. In bispecific antibody-based pretargeting strategies, the use of bivalent haptens improved the efficacy of the tumor targeting, and a 2-step pretargeted radioimmunotherapy strategy is now being tested in cancer patients. Preclinical studies as well as studies on cancer patients have shown that these pretargeting strategies can result in higher radiation doses to the tumor than can directly radiolabeled antitumor antibodies. Here, the development and state of the art of the most effective approaches for pretargeted radioimmunotherapy are reviewed.

  • pretargeting
  • bispecific antibodies
  • avidin
  • streptavidin
  • biotin
  • radioimmunotherapy
  • radionuclide therapy

The concept of targeting radionuclides to tumors using radiolabeled monoclonal antibodies (mAbs) against tumor-associated antigens was proposed more than a century ago (1). With the development of the hybridoma technology (2) and the availability of mAbs against tumor-associated antigens, this concept was investigated scientifically in animal models and in cancer patients. These studies showed that targeting mAbs to tumors is an inefficient process. On intravenous injection, mAbs accumulate in tumors relatively slowly, and several days after injection only a few percent, at most, of the injected dose is localized in the tumor. The inefficiency of this accumulation has been attributed to the presence of various physiologic barriers between the circulation and the tumor cell surface (3). The vascular endothelium, the relatively large transport distances in the tissue, and the enhanced interstitial pressure in the tumor tissue hamper the penetration of mAbs into the tumor tissue to bind to their target antigen. Despite inefficient targeting, good response rates have been obtained with radioimmunotherapy in patients with hematologic tumors. B-cell lymphomas can be treated effectively with radiolabeled mAbs. Overall response rates of 60%–70% have been reported in patients with refractory non-Hodgkin’s lymphoma using radiolabeled anti-CD20 mAbs. The murine anti-CD20 mAb (2B8) labeled with 90Y, designated as 90Y-ibritumomab tiuxetan (Zevalin; IDEC Pharmaceuticals Corp., San Diego, CA), has recently been approved for the treatment of relapsed or refractory low-grade, follicular non-Hodgkin’s lymphoma (4).

Response rates in patients with solid tumors are modest; thus, for these less radiosensitive tumors, more effective targeting of tumors with mAbs is required. The efficacy of radioimmunotherapy therefore has to be further optimized. The driving force of the penetration, diffusion, and accumulation of radiolabeled mAbs in tumor tissue is their sustained high level in the circulation. In contrast, the high residence time of radiolabeled mAbs in the blood correlates with the radiation dose to the bone marrow, the dose-limiting organ in radioimmunotherapy. In fact, this is the most important dilemma in radioimmunotherapy: On the one hand, one aims to optimize the accumulation of the mAb in the tumor; on the other hand, the radiation dose to the bone marrow and, thus, the residence time in the circulation should be minimized.

Several strategies to improve targeting of tumors with radiolabeled mAbs have been developed, such as the use of mAb fragments, the use of high-affinity mAbs, the use of labeling techniques that are stable in vivo, active removal of the radiolabeled mAb from the circulation, and pretargeting strategies.

In pretargeting, the radionuclide is administered separately from the tumor-targeting mAb. In the first step, the unlabeled antitumor mAb is administered and allowed to accumulate in the tumor. In a later phase, preferably when the mAb has cleared from the circulation, the radionuclide is administered as a rapidly clearing agent with high affinity for the unlabeled molecule that was injected in the first phase. Pretargeting can be regarded as in vivo mAb labeling, because the antitumor mAb is radiolabeled after in vivo administration, preferably in the tumor. Here, the pretargeting strategies that have been developed are reviewed.

THE CONCEPT OF PRETARGETING

Conventional mAb targeting using directly radiolabeled mAbs is characterized by slow pharmacokinetics: the half-life of a mAb in the circulation is usually between 2 and 4 d. Such a long residence time in the blood may facilitate the optimal driving force for optimal accretion of the mAbs in the tumor. On the other hand, it also causes relatively high residence times of the radiolabeled mAbs in the nontarget tissues. In pretargeting, the unlabeled mAb is injected in the first phase. After clearance from the blood, the radionuclide is injected in a later phase. The radionuclide is generally administered linked to a relatively small molecule that is cleared rapidly from the blood, in an attempt to maximize accumulation in the tumor while minimizing exposure to the nontarget organs. The radiolabeled ligand should distribute rapidly throughout the body and is to be bound to the prelocalized mAb in the target tissue, whereas the unbound radiolabeled molecule should clear rapidly from the body, preferably through the kidneys. The pretargeting concept was proposed 15 y ago by Goodwin et al., who suggested that tumors be pretargeted with agents with dual specificity (bifunctional mAbs or mAb–avidin conjugates) with affinity for the tumor on the one hand and for the radiolabeled ligand on the other (5,6). Since then, various research groups have tested and optimized a series of pretargeting approaches. Two main approaches based on the interaction between the first and second injectates can be distinguished: avidin–or streptavidin–biotin interaction and mAb–hapten interaction.

PRETARGETING BASED ON BIOTIN AND AVIDIN

Avidin, a minor constituent of the egg white of reptiles, amphibians, and birds, is a glycosylated and positively charged protein that can bind up to 4 molecules of vitamin H, D-biotin (7). The interaction with biotin is noncovalent but extremely avid, the affinity constant (1015 per mole) is 1,000,000-fold higher than that of the antigen–mAb interaction. Functional avidin is a tetramer of identical subunits. Streptavidin is a bacterial analog of avidin with similar biotin-binding characteristics, with less normal tissue retention than that of avidin (8,9).

The first pretargeting studies with biotinylated mAbs aimed to exploit the extremely high affinity of avidin for biotin. In mice and rabbits, the target was pretargeted with biotinylated mAbs, and radiolabeled avidin was administered in the second step. These studies provided proof of principle that radiolabeled avidin could accumulate in the biotinylated target (5,10,11). The radiolabeled avidin also bound to the biotinylated mAb in the circulation. An avidin “chase” was given before injection of the radiolabeled avidin to lower the concentration of the biotinylated mAb in the blood. In nude mice with human tumor xenografts, injection of unlabeled avidin before injection of the radiolabeled avidin or streptavidin accelerated the tumor uptake as well as the blood clearance of the radiolabeled avidin or streptavidin (12,13). Furthermore, investigators realized soon thereafter that the rapid pharmacokinetics of biotin would be fully exploited if one pretargeted the tumor with avidin and administered radiolabeled biotin in the last step (14,15).

THE MILAN EXPERIENCE

Since 1988, an Italian group of investigators under the direction of Paganelli has been testing pretargeting strategies based on biotin and avidin, mainly in clinical studies (10). In ovarian cancer patients, they tested a 2-step approach. Biotinylated antifolate receptor mAbs (MOv18) were injected intraperitoneally in 15 patients. Three to 5 d later, 111In-labeled streptavidin (SA) (100–150 μg) was injected intraperitoneally. Tumors were imaged between 2 and 48 h after injection of the radiolabel. Ex vivo measurements of resected tumor samples indicated that activity uptake in the tumors was at least as high as obtained with directly labeled mAbs (0.005–0.3 percentage injected dose per gram [%ID/g]) (16).

In patients with carcinoembryonic antigen (CEA)–producing tumors, the group in Milan tested a 3-step mAb-targeting methodology. This 3-step strategy is schematically summarized in Figure 1. Nineteen patients received a biotinylated anti-CEA mAb (FO23C5) intravenously. After 3 d, unlabeled avidin was injected to clear the biotinylated mAb from the blood. Another 2 d later, patients received 111In-labeled biotin. In all patients with tumors, tumors were detected with reasonable tumor-to-background ratios (17). Similarly, for patients with pulmonary carcinoma on whom the same 3-step injection scheme was used (FO23C5-biotin/avidin/111In-biotin), tumors were imaged in 8 of 10 patients (18). This injection scheme was also applied successfully to detect tumor lesions intraoperatively in rectal cancer patients using a γ-detection probe (19).

FIGURE 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 1.

Schematic representation of 3-step avidin/biotin-based pretargeting. Biotinylated antitumor mAb is injected in first step. Subsequently, avidin is administered to avidinylate tumor, and in last step radiolabeled biotin is injected.

The group in Milan studied this 3-step strategy (mAb-biotin/avidin/radiolabeled biotin) using at least 5 different antitumor mAbs. Neuroendocrine tumors could be visualized using a biotinylated anti–chromogranin A mAb (A11) in the first step and 99mTc-biotin in the last step (20–22). In patients with uveal melanoma, the 3-step approach, using a biotinylated mAb against a melanoma-associated antigen (HMW-MAA, 225-28S), was compared with the 1-step method (99mTc-labeled 225-28S mAb) (23). Intrapatient comparisons for 15 patients showed that the 3-step method effectively reduced background activity, resulting in tumor-to-nontumor ratios that were twice as high as those for the 1-step method (24).

The group’s 99mTc-labeled biotin, although less suitable for imaging abdominal tumor masses because of its hepatobiliary route of clearance, was successfully used in combination with biotinylated antitenascin mAb (BC2) to visualize cerebral gliomas (25).

These studies in cancer patients showed that biotin–avidin pretargeting could improve tumor-to-background ratios. In addition, the studies demonstrated that the results are markedly affected by the dosing and timing of the reagents: In general, a 1- to 2-mg dose of the mAb followed by approximately 5 mg of avidin and a low dose (<0.1 mg) of radiobiotin, with at least a 2-d interval between the injections, was optimal. Furthermore, the characteristics of the antitumor mAb also determined the targeting efficiency. Obviously, mAbs that are rapidly internalized by the tumor cell are less suitable for application in the 3-step approach, because with these mAbs, the biotin residues are not optimally presented on the surface of the tumor cells. Moreover, in vitro studies indicated that biotinylated MOv18 was internalized by the target cell after binding of SA. The relatively low tumor-to-background ratios obtained with the 3-step method in ovarian cancer patients using biotinylated MOv18 may be due to the internalization of the antigen–MOv18–SA complex (26).

The circulatory half-life of avidin is much shorter than that of SA. Therefore, avidin has more optimal characteristics as a clearing agent: It can rapidly bind the biotinylated mAbs in the circulation, and the avidin that does not bind any biotinylated mAb also clears to the liver. In contrast, the relatively long-circulating SA has more optimal characteristics to avidinylate the tumor that was pretargeted with biotinylated mAb. During the course of their studies, the group in Milan further optimized the 3-step pretargeting injection scheme (mAb-biotin/avidin/radiolabeled biotin) by replacing the second step with the sequential injection of avidin and SA. With this 4-step injection scheme (mAb-biotin/avidin/SA/111In-biotin), tumor lesions were visualized in 30 ovarian cancer patients (27). Lesions were visualized in all patients with tumors, and no false-negative results were obtained.

Subsequently, an extra clearing agent was introduced to remove the remaining SA from the circulation. Biotinylated albumin was injected just before administration of the radiolabeled biotin. Optimal tumor-to-background ratios were obtained with this 5-step injection scheme (mAb-biotin/avidin/SA/biotinylated albumin/radiolabeled biotin), as represented schematically in Figure 2.

FIGURE 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 2.

Schematic representation of 5-step SA/biotin- or avidin/biotin-based pretargeting strategy. First, biotinylated mAb is injected. Then, avidin is administered to clear biotinylated mAb from circulation. Streptavidin is injected in third step to avidinylate tumor. Circulating SA is cleared with biotinylated albumin, and radiolabeled biotin is then injected.

This 5-step strategy has now been developed for radioimmunotherapy of cancer (28,29). Patients with grade III or IV glioma received biotinylated antitenascin mAb (BC4, 35 mg/m2) intravenously. One day later (24–36 h), they received 30 mg of avidin followed 30 min later by 50 mg of SA. Yet another day later (18–24 h), patients received 20 mg of biotinylated human albumin to reduce the levels of circulating SA. Ten minutes after this second chase, the radiolabeled biotin was injected (2 mg of biotin labeled with 4.4- to 5.9-GBq 90Y, mixed with 50 μg of biotin labeled with 74- to 111-MBq 111In) (Fig. 3) (28,29). The use of dodecanetetraacetic acid (DOTA) as a chelator to label biotin with 90Y was shown to be inevitable, because with diethylenetriaminepentaacetic acid (DTPA)–biotin approximately 5% of the 90Y was released in vivo, causing a considerable additive radiation dose to the red marrow (30). The treatment of 48 glioma patients with therapeutic doses of 90Y-DOTA–biotin (2.20–2.96 GBq/m2) has been reported. Therapeutic responses were observed during the phase I dose escalation study (4 complete responses, 2 partial responses) (29). The approach has also been tested in patients with recurrent glioma after a second surgical debulking. In these patients, the reagents were administered directly into the surgical cavity. During dose escalation (0.55–1.11 MBq) in 24 patients, the overall response rate of this locoregional pretargeted radioimmunotherapy was 25% (2 partial responses, 4 moderate responses) (28). Recently, a radioimmunotherapy study was completed using the same therapeutic regimen in high-grade glioma patients with no evidence of disease after surgery and radiotherapy. In this nonrandomized study, the median disease-free interval in patients with glioblastoma (n = 19) and grade III glioma (n = 17) was 28 mo (range, 9–59 mo) and 56 mo (range, 15–60 mo), respectively (31). These median survival intervals are much longer than those of glioma patients who did not receive this adjuvant treatment; thus, a randomized trial is warranted.

FIGURE 3.
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 3.

Anterior whole-body images of patient with recurrent glioma who underwent 5-step pretargeted radioimmunotherapy (2.22 MBq/m2 90Y-DOTA-biotin). 111In-DOTA-biotin (74 MBq) was coadministered to allow scintigraphic imaging. Images were acquired 1 h (left) and 22 h (right) after administration of radiolabeled biotin. On image acquired 22 h after injection, tumor is clearly visualized (arrow).

The relatively slow pharmacokinetics of SA make this molecule more suitable than avidin to avidinylate the tumor. However, Chinol et al. have shown that SA is more immunogenic (32). Streptavidin is a bacterial protein that does not have a mammalian analog and, thus, cannot be humanized. Pegylation of avidin increased the plasma half-life and reduced the immunogenicity of avidin; however, pegylation reduced the biotin-binding capacity of the molecule.

THE NeoRx APPROACH

Another pretargeting strategy based on SA and biotin was developed at NeoRx Corp. (Seattle, WA) (Fig. 4). In this 3-step approach, the tumor is pretargeted with a mAb–SA conjugate. In the second step, this conjugate is cleared from the circulation with a chase of galactosylated biotin-albumin. This agent complexes with the mAb–SA conjugate in the circulation. Subsequently, the complex is rapidly cleared and metabolized in the liver because of the interaction of the galactose groups with the asialoglycoprotein receptor on hepatocytes (33). In the last step, radiolabeled DOTA-biotin is administered. This injection scheme was tested using an anti-Ep-CAM mAb (NR-LU-10) in nude mice with LS180 human colon carcinoma xenografts (34). In this model, tumor uptake 1 and 2 d after injection of the radiolabeled DOTA-biotin (%ID/g) was in the same range as that of the directly labeled NR-LU-10 mAb, whereas blood levels were at least 10 times lower. Dosimetric analysis of the biodistribution data indicated that at equal blood and marrow doses, the radiation dose to the tumor obtained with the pretargeting approach was 28 times (!) higher than the dose obtained with the 90Y-labeled mAb. In 10 of 10 mice with established human small cell lung cancer or colon cancer xenografts, a single dose of pretargeted radioimmunotherapy with 90Y-DOTA-biotin (22.2–29.6 MBq) ablated the tumors.

FIGURE 4.
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 4.

Schematic representation of 3-step SA/biotin-based pretargeting strategy. mAb–SA conjugate is injected, followed by galactosylated albumin-biotin as clearing agent. In third step, radiolabeled biotin is injected.

On the basis of the excellent targeting and therapeutic efficacy of the pretargeting approach based on NR-LU-10 and SA in nude mice, this 3-step approach was further developed in clinical studies. Forty-three patients with adenocarcinomas received 3 subsequent injections: NR-LU-10 mAb–SA conjugate, biotin-galactose-albumin as a clearing agent, and 111In/90Y-DOTA-biotin. The injection schema was optimized with respect to dosing and timing as follows: mAb–SA conjugate (168–600 mg) Embedded Image clearing agent (110–600 mg) Embedded Image DOTA-biotin (0.5–2 mg).

Initially, one aimed to saturate the tumor with mAb–SA conjugate. However, at higher doses (>400 mg), high uptake of the radiolabel in the kidneys was observed, most likely because of the known antigen expression in the kidneys (35). A bolus injection of a 10-fold molar excess in the circulation of the clearing agent effectively cleared the mAb–SA conjugate to the liver (400 mg). Finally, optimal tumor doses were obtained at a relatively low dose of DOTA-biotin (0.5 mg). When this injection was given relatively early after injection of the clearing agent (4 h), uptake of the radiolabel in the liver was relatively high. Thus, the optimal injection scheme was defined as 400 mg of mAb–SA conjugate, followed at 48 h by 400 mg of clearing agent. The radiobiotin (0.5 mg) is administered 24 h after the clearing agent (36). A subsequent activity dose escalation study found that at doses exceeding 4.1 GBq/m2, 90Y-DOTA-biotin dose-limiting gastrointestinal toxicity (grade III/IV diarrhea) occurred because of reactivity of the mAb with normal gastrointestinal tract epithelium (37).

The therapeutic efficacy of the optimized 3-step strategy was determined in a phase II study on 25 patients with metastatic colon cancer. The patients received 400 mg of NR-LU-10–SA conjugate intravenously; 2 d later, 400 mg of biotin-galactose-albumin were administered; and another day later, 4.1 GBq/m2 of 90Y-DOTA-biotin were given (38). Two patients had a partial response (overall response rate, 8%): In the 2 patients who responded, the estimated dose to the tumor was 4,000 and 6,000 cGy (39). Within 4 wk, antibodies against the murine mAb, SA, and mAb–SA conjugate were detected in the serum of all patients who received the 3 consecutive injections (38).

In the phase II study, patients received a relatively high dose to the small-intestine wall (mean dose, 13,334 cGy) because of the reactivity of the NR-LU-10 mAb with the bowel epithelium, and consequently, one third of the patients experienced grade III/IV diarrhea. In addition, the radiation dose to the kidneys in these patients was also relatively high (1,606–3,454 cGy) because of Ep-cam antigen expression in the tubular epithelium. From these phase I/II studies, it was concluded that with this 3-step pretargeting radioimmunotherapy approach, the radiation doses to the tumor can be enhanced. However, the NR-LU-10 mAb is unsuitable for this application because of its reactivity with the normal gastrointestinal epithelium and collecting tubules in the kidneys. Therefore, the approach was tested using an anti-CD20–SA conjugate for the treatment of patients with non-Hodgkin’s lymphoma. Press et al. showed that the therapeutic efficacy of the 3-step approach in mice with Ramos lymphoma xenografts was superior to that of the 90Y-labeled anti-CD20 mAb (40). The 3-step strategy was tested using the chimeric anti-CD20 mAb (C2B8 = rituximab) conjugated with SA in patients with non-Hodgkin’s lymphoma (41). Dosimetric analysis of the images obtained after injection of 111In-DOTA-biotin indicated that pretargeting improved the radiation absorbed doses to the tumor lesions; the median tumor–to–whole-body dose was 35:1 in these patients. Forty percent of the lesions in these patients (n = 30) would have received a dose exceeding 3,000 cGy if 1.85 GBq had been administered. In the 7 patients who actually received a therapeutic activity dose of 90Y-DOTA-biotin (1.11–1.85 GBq/m2), 3 complete responses and 1 partial response were observed (42).

THE ROLE OF ENDOGENOUS BIOTIN AND BIOTINIDASE

As indicated above, biotin or vitamin H has a physiologic role in vertebrates. Several studies have shown that endogenous biotin levels (10−8–10−7 mol/L) could affect the efficacy of SA- or avidin-based pretargeting strategies (43,44). In a study on mice, Rusckowski et al. observed that a tumor pretargeted with a mAb–SA conjugate could bind biotin (exogenously administered) only when the mice were depleted of endogenous biotin (by sequential intraperitoneal injections of avidin) (43). Sharkey et al. tested a 3-step pretargeting approach similar to that developed by the NeoRx group, using an SA–anti-CEA mAb (MN-14) conjugate in nude mice with CEA-expressing GW-39 tumors. In that model, the mAb–SA conjugate could not be cleared from the circulation using galactosylated albumin-biotin, unless the animals were fed a biotin-deficient diet (44). These experiments showed that endogenous biotin levels can markedly interfere in avidin- or SA-based pretargeting strategies. Whether this also applies in studies of cancer patients is still a matter of debate.

In addition, it has been suggested that radiolabeled biotin compounds (DTPA-biotin, DOTA-biotin) can be hydrolyzed by endogenous biotinidase. The primary function of the enzyme is to cleave the biotin amide bond linking biotin and lysine in biocytin in such a way that the essential vitamin H can be recycled. Biotinidase is present in serum and tissues of both animals and humans in nanomolar concentrations. Several investigators have successfully changed the structure of the biotin derivatives used in pretargeting to make the compound unsusceptible toward biotinidase. Chemically modifying the carbon atom α to the biotin amide bond has been shown to effectively block biotinidase cleavage of the biotin amide bond (45,46).

Improved reagents for this 3-step pretargeting radioimmunotherapy strategy have been developed. In the study on patients with non-Hodgkin’s lymphoma, a synthetic clearing agent (biotin-N-acetyl-galactosamine) was used (47). Studies with radiolabeled anti-CD20–SA conjugates showed that this clearing agent removed more than 95% of the conjugate from the circulation. Recently, the synthesis of mAb–SA fusion proteins by genetic engineering has been described (48–50). A fusion protein of the humanized NR-LU-10 single-chain mAb and SA (scFv–SA) was produced and was shown to specifically trap radiolabeled biotin in the tumor in nude mice with SW1222 human colon carcinoma xenografts (48). In addition, for lymphoma targeting, a tetravalent single-chain mAb fusion protein of the murine single-chain CD20 mAb and SA was produced (50). In contrast to the chemical mAb–SA conjugates, these agents have a well-defined homogeneous composition and are relatively easy to manufacture. The latter construct is now in clinical trials.

In summary, 3-step radioimmunotherapy using mAb–SA conjugates, a clearing agent, and radiobiotin can enhance the radiation dose to the tumor, in comparison with the dose delivered by radioimmunotherapy using directly labeled mAbs. The first phase-I/II radioimmunotherapy studies have shown that the approach can induce therapeutic responses. The approach requires the use of mAbs that can specifically avidinylate the tumor. Well-defined agents (mAb–SA conjugate, clearing agent, and biotinidase-resistant biotin-DOTA) and accurate dosing and timing of the injections are crucial. The role of endogenous biotin in patients has yet to be determined. Development of anti-SA mAbs will preclude multiple treatments.

PRETARGETING WITH BISPECIFIC mAbs (bsmAbs)

The first studies to use mAb constructs with dual reactivity in a pretargeting strategy were reported in 1985. A group of investigators at Stanford University and the University of California (51,52) produced mAbs against chelated radiometals and tested the concept in mice with syngeneic KHJJ tumors. In the initial studies, antibenzyl ethylenediaminetetraacetic acid (EDTA) mAbs were complexed with the 111In-labeled chelate in vitro and subsequently were injected into tumor-bearing mice. Complex formation with the mAb markedly enhanced the circulatory half-life of the 111In-labeled chelate. Consequently, uptake of the mAb–chelate complex in the tumor was 50-fold higher than that of the 111In-labeled chelate alone (52). In later studies, an actual pretargeting approach was tested with these antichelate mAbs. The unlabeled antichelate mAb was injected intravenously in mice with KHJJ tumors, followed by an injection with the radiolabeled chelate (53). These studies showed that tumor targeting could be markedly improved when the antichelate mAb was cleared from the circulation before injection of the radiolabeled chelate. For this purpose, Goodwin et al. used transferrin substituted with multiple EDTA haptens as a clearing agent. Use of the clearing agent caused a 3-fold reduction of uptake in the tumor. However, because of more rapid clearance of the radiolabeled chelate from the blood, tumor-to-blood ratios increased 13-fold (54). This approach was further developed for radioimmunotherapy by developing a mAb specifically reactive with DOTA labeled with yttrium. KHJJ tumors in mice were pretargeted with the anti-DOTA mAb. One day later, circulating mAb was cleared by injection of transferrin substituted with multiple DOTA haptens, followed by injection of 88Y-DOTA 1 h later (55). Three hours after injection of the radiolabel, tumor uptake was 1.7 %ID/g and a tumor-to-blood ratio of 16 was measured, indicating specific targeting of the tumor.

In the experiments described above, the mAbs used to pretarget the tumor did not have any affinity for the tumor, and accumulation of the antichelate mAbs in the tumor was dependent on the nonspecific accumulation in the tumor caused by enhanced vascular permeability in the tumor. Specific pretargeting of tumors requires the production of mAbs with dual specificity: affinity for the tumor-associated antigen on the one hand and affinity for the radiolabeled hapten on the other. Several methods have been developed to produce such bifunctional mAbs: Heteroconjugates can be produced by chemical cross-linking of 2 mAbs; in general, 1:1 heteroconjugates of mAbs are relatively difficult to synthesize. By chemical cross-linking of the Fab′ fragments of 2 mAbs, F(ab′)2 bsmAb fragments can be produced (56). By fusion of 2 hybridoma cell lines producing 2 different mAbs, quadroma cell lines can be selected that secrete (among others) bispecific IgG molecules (57); in general, purification of the bsmAbs from the quadroma supernatant (containing 10 different IgG-like molecules) is laborious, but this method does not suffer from batch-to-batch variation, as do the chemical methods. By genetic engineering techniques, fusion proteins can be produced containing the antigen-binding regions of 2 mAbs (58).

At Hybritech Inc. (San Diego, CA), a 2-step system based on an anti-CEA (ZCE-025) × anti-111In-benzyl-EDTA Fab′ × Fab′ chemically synthesized bsmAb and an 111In-labeled EDTA derivative (111In-EOTUBE) was developed (59). In mice, the radiolabeled chelate, complexed with bsmAb F(ab′)2 to prolong the plasma half-life of the chelate, was administered 24 h after injection of the bsmAb. One day after injection of 111In-EOTUBE, uptake in the tumor was 18.5 %ID/g, and the blood level was as low as 1.3 %ID/g, indicating efficient tumor targeting. This approach was tested on 14 patients with recurrent colon carcinoma. Scintigraphic imaging visualized 20 of 21 known lesions. Nine occult lesions were imaged, of which 8 could be confirmed.

A similar approach was developed by a group in France (Fig. 5). Chemically produced Fab′–Fab′ bsmAbs were constructed from antitumor mAbs on the one hand and antichelate mAbs on the other. Subcutaneous A375 melanoma tumors pretargeted with antitumor × anti-DTPA F(ab′)2 bsmAb could be targeted with 111In-labeled DTPA. Interestingly, this study showed that the use of a peptide substituted with 2 DTPA moieties (DTPA-Tyr-Lys-DTPA) accreted more efficiently in the tumor (3.5 %ID/g 24 h after injection) than did monovalent DTPA-111In (2.8 %ID/g 24 h after injection) (60). It was hypothesized that at the tumor cell surface, the bivalently substituted peptide is bound by 2 bsmAbs, resulting in more avid binding of the radiolabeled peptide, as depicted in Figure 5. This so-called affinity enhancement system also improved the tumor uptake in other mouse tumor models using bsmAb-based 2-step targeting (61,62). Le Doussal et al. demonstrated improved binding and retention of bivalent peptides (i.e., with 2 haptens) to pretargeted tumor cells in vitro (60,61,63) and elegantly showed that the spacing between the 2 haptens needs to be designed with care: Di- and tripeptides such as tyrosyl-lysine and lysyl-tyrosyl-lysine with 2 hapten-substituted amino groups had ideal characteristics for this application (62,64). Goodwin et al., in their murine KHJJ model, also obtained improved tumor uptake using a bivalent DOTA construct (1.7 %ID/g vs. 4.4 %ID/g 3 h after injection) named Janus-DOTA, after the Roman deity with 2 faces (55). In our renal cell carcinoma nude mouse model using biologically produced bsmAbs, application of a bivalent hapten, Phe-Lys(DTPA-111In)-Tyr-Lys(DTPA-111In), improved uptake of the radiolabel in the tumor by a factor of 30 (!) (2.2 %ID/g vs. 77.5 %ID/g at 1 h after injection) (Fig. 6) (52). That study also showed that pretargeting with bsmAbs (in comparison with directly labeled mAbs) could improve not only tumor-to-background ratios but also uptake of radiolabel by tumor in terms of %ID/g during the first 24 h.

FIGURE 5.
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 5.

Schematic representation of 2-step bsmAb-based pretargeting strategy. Tumor is pretargeted with antihapten × antitumor F(ab′)2 bsmAb. In second step, radiolabeled bivalent hapten is administered. Note bivalent binding of bivalent hapten at tumor cell surface.

FIGURE 6.
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 6.

Scintigraphic images of nude mice with subcutaneous human renal cell carcinoma xenografts in right flank (arrows). Mice were injected intravenously with 15 μg G250 × DTIn-1 bsmAb. Three days later, mice intravenously received 10 ng of tetrapeptide substituted with 2 DTPA moieties and labeled with 1.85 MBq of 111In. Images were acquired at 1, 4, 24, and 96 h after injection (p.i.).

Interestingly, in most studies using bsmAbs to pretarget the tumor, the bsmAbs were not cleared from the circulation before injection of the radiolabeled (bivalent) peptide. In contrast, when the tumor is pretargeted with avidin (i.e., is avidinylated), the use of a clearing agent appeared to be indispensable. Fab′–Fab′ bsmAbs rapidly clear from the blood. Therefore, blocking the remaining antihapten activity in the circulation appears to be superfluous (60,62,65). In addition, the difference in affinity between the hapten–mAb (10−8 per mole) and the biotin–avidin (10−15 per mole) interactions might also play a role. Intravenous injection of radiolabeled biotin in circulation that still contains significant levels of avidin or streptavidin will lead to the formation of stable biotin–avidin or biotin–streptavidin complexes in the circulation. Depending on the antihapten mAb used, the mAb–hapten complexes formed in the circulation are relatively labile. As a result, during the first few hours after injection of the radiolabeled peptide, the peptide–mAb complexes dissociate and the peptide is cleared through the kidneys (52). The fact that, in bsmAb-based pretargeting strategies, the clearing step can be omitted simplifies the introduction of the approach into the clinic, as dosing and timing of the clearing agent are a critical step that requires careful optimization. Overdosing of the blocking agent may block the binding sites in the tumor and may thus reduce tumor targeting (66).

In preclinical studies, the French group has shown that its pretargeting strategy could improve radioimmunotherapy (67–73). In these studies, the tumor was pretargeted with the anti-CEA × anti-DTPA Fab′–Fab′ bsmAb, and 48 h later a therapeutic dose of 131I-labeled di-DTPA-tyrosyl-lysine was administered. In mice with medullary thyroid carcinoma (70,71) or colon carcinoma (67–69), the therapeutic efficacy of 2-step pretargeted radioimmunotherapy was superior to that of 131I-labeled anti-CEA mAbs (F(ab′)2 or IgG). Recently, a di-DTPA substituted peptide was developed that could be radiolabeled with 188Re, allowing the use of this generator-produced β-emitter in pretargeted radioimmunotherapy (74,75).

These promising data obtained in nude mouse tumor models encouraged the French group to test this bsmAb-based 2-step pretargeting approach in cancer patients. In these studies, the chemically produced anti-CEA (clone F6) × anti-DTPA-In (clone 734) F(ab′)2 bsmAb is injected in the first step (0.1 mg/kg). Four to 5 d later, 111In-labeled di-DTPA-tyrosyl-lysine is injected. In the initial studies, the French group showed that the approach could improve radioimmunoscintigraphy of CEA-expressing tumors. In patients with primary colorectal carcinomas (n = 11), uptake of the 111In-labeled di-DPTA peptide (0.002–0.018 %ID/g) was in the same range as uptake of the 111In-labeled F(ab′)2 anti-CEA mAb, whereas ratios of tumor to normal tissue were significantly higher (65). An immunoscintigraphy study in patients with recurrent colorectal cancer indicated that the 111In-diDTPA was taken up mainly in the periphery of liver metastases, whereas uptake in the pelvic lesions was generally higher (76). A study of 12 patients with non–small cell lung carcinoma also showed that the 2-step approach was better than conventional immunoscintigraphy for staging (77). In patients with medullary thyroid carcinoma, uptake of 111In-diDTPA in tumor lesions was relatively high (0.003–0.139 %ID/g; mean, 0.039 %ID/g) (78). Two-step immunoscintigraphy in 44 patients with medullary thyroid carcinoma revealed that the method is sensitive for visualizing occult metastases. In 21 of 29 patients with elevated calcitonin but without known tumor sites, occult metastases were visualized (79).

bsmAb-BASED PRETARGETED RADIOIMMUNOTHERAPY IN PATIENTS

Currently, this bsmAb-based pretargeting method for radioimmunotherapy is being tested in cancer patients. In this system, 111In could not simply be substituted with 90Y, because the anti-DTPA mAb used (clone 734) is specifically reactive with cyclic anhydride DTPA, which was reacted with an amino group and subsequently labeled with 111In. First, such a DTPA moiety labeled with 90Y will not be stable in vivo. Second, the 734 mAb has a reduced affinity for DTPA labeled with 90Y. Therefore, for pretargeted radioimmunotherapy, the di-DTPA-tyrosyl-lysine peptide was labeled with 131I. Five patients with medullary thyroid carcinoma and 5 patients with small cell lung carcinoma (SCLC) whose tumors were pretargeted with the anti-CEA × anti-DTPA-indium bsmAb received a diagnostic dose (222–370 MBq) of 131I-labeled di-DTPA. Dosimetric analysis of the images revealed that the radiation dose to the medullary thyroid carcinoma lesions was much higher (range, 113–470 Gy/MBq [4.2–174 cGy/mCi]) than the radiation dose to the SCLC lesions (range, 4.6–22 Gy/MBq [1.7–8 cGy/mCi]), indicating that medullary thyroid carcinoma is a more suitable target for this pretargeted radioimmunotherapy (80). The feasibility and therapeutic efficacy of pretargeted radioimmunotherapy (pretargeting with 20–50 mg of anti-CEA × anti-DTPA-indium bsmAb and with 1.48–3.7 GBq of 131I-di-DTPA 4 d later) was tested in 26 patients with recurrent medullary thyroid carcinoma. Dose-limiting toxicity was hematologic; an activity dose of 1.78 GBq/m2 could be administered safely. The radiation dose to the tumor ranged from 7.9 to 500 Gy/MBq (2.91–184 cGy/mCi). Minor tumor responses were observed in 30% of the patients who could be evaluated (81). As expected, in a pretargeted radioimmunotherapy study in patients with SCLC (n = 14), the radiation doses to the tumor have been lower, 7.0–87 Gy/MBq (2.6–32.2 cGy/mCi) (Fig. 7) (81). Interestingly, the maximum tolerated dose of the 131I-labeled di-DTPA peptide in these patients was much higher (5.55 GBq), possibly because most medullary thyroid carcinoma patients have micrometastatic disease in the bone marrow. In that study on SCLC patients (81), the activity dose is further escalated, until second organ toxicity. From these patients, stem cells are harvested before treatment and reinfused 10–15 d after injection of the radioactivity. So far, 2 of 12 patients who could be evaluated showed a partial response.

FIGURE 7.
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 7.

Scintigraphic images of patient with metastasized SCLC who received 100 mg/m2 anti-DTPA × anti-CEA F(ab′)2 bsmAb. Seven days later, therapeutic dose (3.7 GBq) of 131I-labeled bivalent hapten was injected. Anterior (A) and posterior (B) images obtained 5 d after injection of radiolabel clearly show accumulation of radiolabel in SCLC lesions in liver.

This pretargeting approach is being further optimized. The use of histamine-hemisuccinate, instead of DTPA, as a hapten allows the use of other more potent radionuclides, such as 188Re, in this strategy. New DOTA-conjugated peptides are being developed that will allow the use of 90Y and 177Lu (64,72,82). Furthermore, humanized bsmAb constructs are being developed that will prevent the development of human antimurine antibody against the bsmAb, as has been observed in most patients who received the anti-CEA × anti-DTPA F(ab′)2 bsmAb (65). Humanized bsmAbs will allow multiple treatment cycles of pretargeted radioimmunotherapy.

PRETARGETED PET IMAGING

A group at the German Cancer Center in Heidelberg developed agents to apply bsmAb pretargeting for PET using the short-lived positron emitter 68Ga (half-life, 68 min) (83,84). mAbs against a gallium chelate were developed (85). Using these mAbs, antichelate × antitumor bsmAbs were developed either chemically (83,86) or biologically (87). With these bsmAbs, pretargeted PET was tested on nude mice with CD44v6- and MUC1-expressing tumors (83,86,88). Recently, this approach was tested on 10 patients with breast cancer. Patients received 10 mg of anti-MUC1 × anti-Ga-chelate bsmAb intravenously, and 18 h later Ga-chelate–substituted human apotransferrin was injected as a blocking agent. Fifteen minutes afterward, 222–296 MBq 68Ga-chelate were administered. PET images were acquired 60–90 min later. Fourteen of 17 known lesions (25 ± 16 mm) were visualized (84). The relatively low uptake of the 68Ga-chelate in the tumor and the low ratios of tumor to normal breast (0.003 %ID/g and 3.0, respectively) were attributed to the shedding of the MUC1 antigen and the comparatively low affinity of the anti-MUC1 mAb (1.2 × 10−7 per mole).

CONCLUSION

In comparison with directly labeled antitumor mAbs, mAb-based pretargeting strategies can enhance the radiation dose to the tumor in radioimmunotherapy.

Therapeutic studies on various groups of cancer patients have shown that the avidin/biotin- or SA/biotin-based approach developed in Milan can induce meaningful therapeutic responses. The radioimmunotherapeutic approach using the mAb–SA conjugates has been tested in only a limited number of patients using an appropriate mAb, and the therapeutic efficacy has yet to be determined. The latter method has the advantage that only 3 injectates are used and that, therefore, the optimization of this approach in terms of dosing and timing will be less complicated. The availability of a new generation of well-defined reagents for this approach (synthetic clearing agent and mAb–SA fusion proteins) is another important step toward clinical applicability of this approach.

Although pretargeted radioimmunotherapy using bsmAb constructs is still in its early phase, promising results have already been obtained with this approach. A major advantage of this pretargeting strategy is that only 2 reagents, the bsmAb and the radiolabeled bivalent hapten, are used. In addition, with the development of humanized bsmAb constructs, this method makes use of reagents that will not evoke an antibody response in patients. The patient groups that will benefit most from this approach have yet to be determined.

Acknowledgments

The authors thank Drs. Hazel B. Breitz and Robert M. Sharkey for their thoughtful suggestions and Drs. Giovanni Paganelli and Jean-François Chatal for generously providing Figures 3 and 7.

Footnotes

  • Received Mar. 28, 2002; revision accepted Sep. 25, 2002.

    For correspondence or reprints contact: Otto C. Boerman, PhD, Department of Nuclear Medicine, University Medical Center Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

    E-mail: O.Boerman{at}nucmed.umcn.nl

  • ↵* NOTE: FOR CE CREDIT, YOU CAN ACCESS THIS ACTIVITY THROUGH THE SNM WEB SITE (http://www.snm.org/education/ce_online.html) THROUGH MARCH 2004.

REFERENCES

  1. ↵
    Ehrlich P. On immunity with special reference to cell life. In: Himmelweit F, Marquardt M, Dale H, eds. The Collected Papers of Paul Ehrlich, Volume II: Immunology and Cancer Research. London U.K.: Pergamon Press; 1957.
  2. ↵
    Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975; 256: 495–497.
    OpenUrlCrossRefPubMed
  3. ↵
    DeNardo SJ, DeNardo GL, Brush J, Carter P. Phage library-derived human anti-TETA and anti-DOTA ScFv for pretargeting RIT. Hybridoma. 1999; 18: 13–21.
    OpenUrlPubMed
  4. ↵
    Wagner HN Jr, Wiseman GA, Marcus CS, et al. Administration guidelines for radioimmunotherapy of non-Hodgkin’s lymphoma with (90)Y-labeled anti-CD20 monoclonal antibody. J Nucl Med. 2002; 43: 267–272.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    Goodwin D, Meares C, Diamanti C, et al. Use of specific antibody for rapid clearance of circulating blood background from radiolabeled tumor imaging proteins. Eur J Nucl Med. 1984; 9: 209–215.
    OpenUrlCrossRefPubMed
  6. ↵
    Goodwin DA, Mears CF, McTigue M, David GS. Monoclonal antibody hapten radiopharmaceutical delivery. Nucl Med Commun. 1986; 7: 569–580.
    OpenUrlPubMed
  7. ↵
    Lindqvist Y, Schneider G. Protein-biotin interactions. Curr Opin Struct Biol. 1996; 6: 798–803.
    OpenUrlCrossRefPubMed
  8. ↵
    Schechter B, Arnon R, Colas C, Burakova T, Wilchek M. Renal accumulation of streptavidin: potential use for targeted therapy to the kidney. Kidney Int. 1995; 47: 1327–1335.
    OpenUrlCrossRefPubMed
  9. ↵
    Schechter B, Silberman R, Arnon R, Wilchek M. Tissue distribution of avidin and streptavidin injected to mice: effect of avidin carbohydrate, streptavidin truncation and exogenous biotin. Eur J Biochem. 1990; 189: 327–331.
    OpenUrlPubMed
  10. ↵
    Paganelli G, Riva P, Deleide G, et al. In vivo labelling of biotinylated monoclonal antibodies by radioactive avidin: a strategy to increase tumor radiolocalization. Int J Cancer Suppl. 1988; 2: 121–125.
    OpenUrlPubMed
  11. ↵
    Pimm MV, Fells HF, Perkins AC, Baldwin RW. Iodine-131 and indium-111 labelled avidin and streptavidin for pre-targetted immunoscintigraphy with biotinylated anti-tumour monoclonal antibody. Nucl Med Commun. 1988; 9: 931–941.
    OpenUrlCrossRefPubMed
  12. ↵
    Paganelli G, Pervez S, Siccardi AG, et al. Intraperitoneal radio-localization of tumors pre-targeted by biotinylated monoclonal antibodies. Int J Cancer. 1990; 45: 1184–1189.
    OpenUrlPubMed
  13. ↵
    Yao Z, Zhang M, Kobayashi H, et al. Improved targeting of radiolabeled streptavidin in tumors pretargeted with biotinylated monoclonal antibodies through an avidin chase. J Nucl Med. 1995; 36: 837–841.
    OpenUrlAbstract/FREE Full Text
  14. ↵
    Sung C, van Osdol WW, Saga T, Neumann RD, Dedrick RL, Weinstein JN. Streptavidin distribution in metastatic tumors pretargeted with a biotinylated monoclonal antibody: theoretical and experimental pharmacokinetics. Cancer Res. 1994; 54: 2166–2175.
    OpenUrlAbstract/FREE Full Text
  15. ↵
    Sung C, van Osdol WW. Pharmacokinetic comparison of direct antibody targeting with pretargeting protocols based on streptavidin-biotin binding [see comments]. J Nucl Med. 1995; 36: 867–876.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    Paganelli G, Belloni C, Magnani P, et al. Two-step tumour targetting in ovarian cancer patients using biotinylated monoclonal antibodies and radioactive streptavidin. Eur J Nucl Med. 1992; 19: 322–329.
    OpenUrlPubMed
  17. ↵
    Paganelli G, Magnani P, Zito F, et al. Three-step monoclonal antibody tumor targeting in carcinoembryonic antigen-positive patients. Cancer Res. 1991; 51: 5960–5966.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    Dosio F, Magnani P, Paganelli G, Samuel A, Chiesa G, Fazio F. Three-step tumor pre-targeting in lung cancer immunoscintigraphy. J Nucl Biol Med. 1993; 37: 228–232.
    OpenUrlPubMed
  19. ↵
    Di Carlo V, De Nardi P, Stella M, Magnani P, Fazio F. Preoperative and intraoperative radioimmunodetection of cancer pretargeted by biotinylated monoclonal antibodies. Semin Surg Oncol. 1998; 15: 235–238.
    OpenUrlCrossRefPubMed
  20. ↵
    Colombo P, Siccardi AG, Paganelli G, et al. Three-step immunoscintigraphy with anti-chromogranin A monoclonal antibody in tumours of the pituitary region. Eur J Endocrinol. 1996; 135: 216–221.
    OpenUrlAbstract/FREE Full Text
  21. Magnani P, Paganelli G, Siccardi AG, et al. Combined use of 111In-labeled pentetreotide and three-step immunoscintigraphy with antichromogranin A monoclonal antibody in the diagnosis of pituitary adenomas. Cell Biophys. 1994; 24–25: 307–313.
    OpenUrl
  22. ↵
    Siccardi AG, Paganelli G, Pontiroli AE, et al. In vivo imaging of chromogranin A-positive endocrine tumours by three-step monoclonal antibody targeting. Eur J Nucl Med. 1996; 23: 1455–1459.
    OpenUrlCrossRefPubMed
  23. ↵
    Modorati G, Brancato R, Paganelli G, Magnani P, Pavoni R, Fazio F. Immunoscintigraphy with three step monoclonal pretargeting technique in diagnosis of uveal melanoma: preliminary results. Br J Ophthalmol. 1994; 78: 19–23.
    OpenUrlAbstract/FREE Full Text
  24. ↵
    Magnani P, Paganelli G, Modorati G, et al. Quantitative comparison of direct antibody labeling and tumor pretargeting in uveal melanoma. J Nucl Med. 1996; 37: 967–971.
    OpenUrlAbstract/FREE Full Text
  25. ↵
    Paganelli G, Magnani P, Zito F, et al. Pre-targeted immunodetection in glioma patients: tumour localization and single-photon emission tomography imaging of [99mTc]PnAO-biotin. Eur J Nucl Med. 1994; 21: 314–321.
    OpenUrlCrossRefPubMed
  26. ↵
    Casalini P, Luison E, Menard S, Colnaghi MI, Paganelli G, Canevari S. Tumor pretargeting: role of avidin/streptavidin on monoclonal antibody internalization. J Nucl Med. 1997; 38: 1378–1381.
    OpenUrlAbstract/FREE Full Text
  27. ↵
    Magnani P, Fazio F, Grana C, et al. Diagnosis of persistent ovarian carcinoma with three-step immunoscintigraphy. Br J Cancer. 2000; 82: 616–620.
    OpenUrlCrossRefPubMed
  28. ↵
    Paganelli G, Bartolomei M, Ferrari M, et al. Pre-targeted locoregional radioimmunotherapy with 90Y-biotin in glioma patients: phase I study and preliminary therapeutic results. Cancer Biother Radiopharm. 2001; 16: 227–235.
    OpenUrlCrossRefPubMed
  29. ↵
    Paganelli G, Grana C, Chinol M, et al. Antibody-guided three-step therapy for high grade glioma with yttrium-90 biotin. Eur J Nucl Med. 1999; 26: 348–357.
    OpenUrlCrossRefPubMed
  30. ↵
    Cremonesi M, Ferrari M, Chinol M, et al. Three-step radioimmunotherapy with yttrium-90 biotin: dosimetry and pharmacokinetics in cancer patients. Eur J Nucl Med. 1999; 26: 110–120.
    OpenUrlCrossRefPubMed
  31. ↵
    Grana C, Chinol M, Robertson C, et al. Pretargeted adjuvant radioimmunotherapy with yttrium-90-biotin in malignant glioma patients: a pilot study. Br J Cancer. 2002; 86: 207–212.
    OpenUrlCrossRefPubMed
  32. ↵
    Chinol M, Casalini P, Maggiolo M, et al. Biochemical modifications of avidin improve pharmacokinetics and biodistribution, and reduce immunogenicity. Br J Cancer. 1998; 78: 189–197.
    OpenUrlCrossRefPubMed
  33. ↵
    Stockert RJ. The asialoglycoprotein receptor: relationships between structure, function, and expression. Physiol Rev. 1995; 75: 591–609.
    OpenUrlAbstract/FREE Full Text
  34. ↵
    Axworthy DB, Reno JM, Hylarides MD, et al. Cure of human carcinoma xenografts by a single dose of pretargeted yttrium-90 with negligible toxicity. Proc Natl Acad Sci USA. 2000; 97: 1802–1807.
    OpenUrlAbstract/FREE Full Text
  35. ↵
    Breitz HB, Weiden PL, Vanderheyden JL, et al. Clinical experience with rhenium-186-labeled monoclonal antibodies for radioimmunotherapy: results of phase I trials. J Nucl Med. 1992; 33: 1099–1109.
    OpenUrlAbstract/FREE Full Text
  36. ↵
    Breitz HB, Weiden PL, Beaumier PL, et al. Clinical optimization of pretargeted radioimmunotherapy with antibody-streptavidin conjugate and 90Y-DOTA-biotin. J Nucl Med. 2000; 41: 131–140.
    OpenUrlAbstract/FREE Full Text
  37. ↵
    Murtha A, Weiden P, Knox SJ, et al. Phase I dose escalation trial of pretargeted radioimmunotherapy (PRIT) with 90yttrium [abstract]. Proc Am Soc Clin Oncol. 1998; 17: 438.
    OpenUrl
  38. ↵
    Knox SJ, Goris ML, Tempero M, et al. Phase II trial of yttrium-90-DOTA-biotin pretargeted by NR-LU-10 antibody/streptavidin in patients with metastatic colon cancer. Clin Cancer Res. 2000; 6: 406–414.
    OpenUrlAbstract/FREE Full Text
  39. ↵
    Breitz HB, Fisher DR, Goris ML, et al. Radiation absorbed dose estimation for 90Y-DOTA-biotin with pretargeted NR-LU-10/streptavidin. Cancer Biother Radiopharm. 1999; 14: 381–395.
    OpenUrlPubMed
  40. ↵
    Press OW, Corcoran M, Subbiah K, et al. A comparative evaluation of conventional and pretargeted radioimmunotherapy of CD20-expressing lymphoma xenografts. Blood. 2001; 98: 2535–2543.
    OpenUrlAbstract/FREE Full Text
  41. ↵
    Weiden PL, Breitz HB, Press O, et al. Pretargeted radioimmunotherapy (PRIT) for treatment of non-Hodgkin’s lymphoma (NHL): initial phase I/II study results. Cancer Biother Radiopharm. 2000; 15: 15–29.
    OpenUrlCrossRefPubMed
  42. ↵
    Weiden PL, Breitz HB. Pretargeted radioimmunotherapy (PRIT) for treatment of non-Hodgkin’s lymphoma (NHL). Crit Rev Oncol Hematol. 2001; 40: 37–51.
    OpenUrlPubMed
  43. ↵
    Rusckowski M, Fogarasi M, Fritz B, Hnatowich DJ. Effect of endogenous biotin on the applications of streptavidin and biotin in mice. Nucl Med Biol. 1997; 24: 263–268.
    OpenUrlCrossRefPubMed
  44. ↵
    Sharkey RM, Karacay H, Griffiths GL, et al. Development of a streptavidin-anti-carcinoembryonic antigen antibody, radiolabeled biotin pretargeting method for radioimmunotherapy of colorectal cancer: studies in a human colon cancer xenograft model. Bioconjug Chem. 1997; 8: 595–604.
    OpenUrlCrossRefPubMed
  45. ↵
    Wilbur DS, Hamlin DK, Chyan MK, Kegley BB, Pathare PM. Biotin reagents for antibody pretargeting. 5. Additional studies of biotin conjugate design to provide biotinidase stability. Bioconjug Chem. 2001; 12: 616–623.
    OpenUrlCrossRefPubMed
  46. ↵
    Gustavson LM, Su F-M, Reno JM, et al. Design and synthesis of metabolically stable chelate-biotin conjugates for pretargeting tumor radioimmunotherapy. In: Proceedings of the 209th meeting of the American Chemical Society; April 1995; Anaheim, CA.
  47. ↵
    Theodore L, Axworthy D, Reno J, inventors; NeoRx Corporation, assignee. Small molecular weight ligand-hexose containing clearing agent. US patent 6,075,010. June 13, 2000.
  48. ↵
    Goshorn S, Sanderson J, Axworthy D, Lin Y, Hylarides M, Schultz J. Preclinical evaluation of a humanized NR-LU-10 antibody-streptavidin fusion protein for pretargeted cancer therapy. Cancer Biother Radiopharm. 2001; 16: 109–123.
    OpenUrlCrossRefPubMed
  49. Hylarides MD, Mallett RW, Meyer DL. A robust method for the preparation and purification of antibody/streptavidin conjugates. Bioconjug Chem. 2001; 12: 421–427.
    OpenUrlCrossRefPubMed
  50. ↵
    Schultz J, Lin Y, Sanderson J, et al. A tetravalent single-chain antibody-streptavidin fusion protein for pretargeted lymphoma therapy. Cancer Res. 2000; 60: 6663–6669.
    OpenUrlAbstract/FREE Full Text
  51. ↵
    Reardan DT, Meares CF, Goodwin D, et al. Antibodies against metal chelates. Nature. 1985; 316: 265–268.
    OpenUrlCrossRefPubMed
  52. ↵
    Boerman OC, Kranenborg MH, Oosterwijk E, et al. Pretargeting of renal cell carcinoma: improved tumor targeting with a bivalent chelate. Cancer Res. 1999; 59: 4400–4405.
    OpenUrlAbstract/FREE Full Text
  53. ↵
    Winthrop MD, DeNardo SJ, DeNardo GL. Development of a hyperimmune anti-MUC-1 single chain antibody fragments phage display library for targeting breast cancer. Clin Cancer Res. 1999; 5: 3088s–3094s.
    OpenUrlAbstract/FREE Full Text
  54. ↵
    Goodwin DA, Meares CF, McCall MJ, McTigue M, Chaovapong W. Pre-targeted immunoscintigraphy of murine tumors with indium-111-labeled bifunctional haptens. J Nucl Med. 1988; 29: 226–234.
    OpenUrlAbstract/FREE Full Text
  55. ↵
    Goodwin DA, Meares CF, Watanabe N, et al. Pharmacokinetics of pretargeted monoclonal antibody 2D12.5 and 88Y-Janus-2-(p-nitrobenzyl)-1, 4, 7, 10-tetraazacyclododecanetetraacetic acid (DOTA) in BALB/c mice with KHJJ mouse adenocarcinoma: a model for 90Y radioimmunotherapy. Cancer Res. 1994; 54: 5937–5946.
    OpenUrlAbstract/FREE Full Text
  56. ↵
    Nolan O, O’Kennedy R. Chemical production of bifunctional antibodies [abstract]. Biochem Soc Trans. 1992; 20: 60S.
    OpenUrlFREE Full Text
  57. ↵
    Nolan O, O’Kennedy R. Bifunctional antibodies: concept, production and applications. Biochim Biophys Acta. 1990; 1040: 1–11.
    OpenUrlCrossRefPubMed
  58. ↵
    Kriangkum J, Xu B, Nagata LP, Fulton RE, Suresh MR. Bispecific and bifunctional single chain recombinant antibodies. Biomol Eng. 2001; 18: 31–40.
    OpenUrlCrossRefPubMed
  59. ↵
    Stickney DR, Anderson LD, Slater JB, et al. Bifunctional antibody: a binary radiopharmaceutical delivery system for imaging colorectal carcinoma. Cancer Res. 1991; 51: 6650–6655.
    OpenUrlAbstract/FREE Full Text
  60. ↵
    Le Doussal JM, Gruaz-Guyon A, Martin M, Gautherot E, Delaage M, Barbet J. Targeting of indium 111-labeled bivalent hapten to human melanoma mediated by bispecific monoclonal antibody conjugates: imaging of tumors hosted in nude mice. Cancer Res. 1990; 50: 3445–3452.
    OpenUrlAbstract/FREE Full Text
  61. ↵
    Le Doussal JM, Gautherot E, Martin M, Barbet J, Delaage M. Enhanced in vivo targeting of an asymmetric bivalent hapten to double-antigen-positive mouse B cells with monoclonal antibody conjugate cocktails. J Immunol. 1991; 146: 169–175.
    OpenUrlAbstract
  62. ↵
    Le Doussal JM, Martin M, Gautherot E, Delaage M, Barbet J. In vitro and in vivo targeting of radiolabeled monovalent and divalent haptens with dual specificity monoclonal antibody conjugates: enhanced divalent hapten affinity for cell-bound antibody conjugate. J Nucl Med. 1989; 30: 1358–1366.
    OpenUrlAbstract/FREE Full Text
  63. ↵
    Le Doussal JM, Barbet J, Delaage M. Bispecific-antibody-mediated targeting of radiolabeled bivalent haptens: theoretical, experimental and clinical results. Int J Cancer Suppl. 1992; 7: 58–62.
    OpenUrlPubMed
  64. ↵
    Janevik-Ivanovska E, Gautherot E, Hillairet de Boisferon M, et al. Bivalent hapten-bearing peptides designed for iodine-131 pretargeted radioimmunotherapy. Bioconjug Chem. 1997; 8: 526–533.
    OpenUrlCrossRefPubMed
  65. ↵
    Le Doussal JM, Chetanneau A, Gruaz-Guyon A, et al. Bispecific monoclonal antibody-mediated targeting of an indium-111-labeled DTPA dimer to primary colorectal tumors: pharmacokinetics, biodistribution, scintigraphy and immune response. J Nucl Med. 1993; 34: 1662–1671.
    OpenUrlAbstract/FREE Full Text
  66. ↵
    Kranenborg MH, Boerman OC, Oosterwijk-Wakka JC, de Weijert MC, Corstens FH, Oosterwijk E. Two-step radio-immunotargeting of renal-cell carcinoma xenografts in nude mice with anti-renal-cell-carcinoma X anti-DTPA bispecific monoclonal antibodies. Int J Cancer. 1998; 75: 74–80.
    OpenUrlCrossRefPubMed
  67. ↵
    Gautherot E, Rouvier E, Daniel L, et al. Pretargeted radioimmunotherapy of human colorectal xenografts with bispecific antibody and 131I-labeled bivalent hapten. J Nucl Med. 2000; 41: 480–487.
    OpenUrlAbstract/FREE Full Text
  68. Gautherot E, Le Doussal JM, Bouhou J, et al. Delivery of therapeutic doses of radioiodine using bispecific antibody-targeted bivalent haptens. J Nucl Med. 1998; 39: 1937–1943.
    OpenUrlAbstract/FREE Full Text
  69. ↵
    Gautherot E, Bouhou J, Le Doussal JM, et al. Therapy for colon carcinoma xenografts with bispecific antibody-targeted, iodine-131-labeled bivalent hapten. Cancer. 1997; 80: 2618–2623.
    OpenUrl
  70. ↵
    Kraeber-Bodere F, Faivre-Chauvet A, Sai-Maurel C, et al. Toxicity and efficacy of radioimmunotherapy in carcinoembryonic antigen-producing medullary thyroid cancer xenograft: comparison of iodine 131-labeled F(ab′)2 and pretargeted bivalent hapten and evaluation of repeated injections. Clin Cancer Res. 1999; 5: 3183s–3189s.
    OpenUrlAbstract/FREE Full Text
  71. ↵
    Kraeber-Bodere F, Faibre-Chauvet A, Sai-Maurel C, et al. Bispecific antibody and bivalent hapten radioimmunotherapy in CEA-producing medullary thyroid cancer xenograft. J Nucl Med. 1999; 40: 198–204.
    OpenUrlAbstract/FREE Full Text
  72. ↵
    Hosono M, Hosono MN, Kraeber-Bodere F, et al. Two-step targeting and dosimetry for small cell lung cancer xenograft with anti-NCAM/antihistamine bispecific antibody and radioiodinated bivalent hapten. J Nucl Med. 1999; 40: 1216–1221.
    OpenUrlAbstract/FREE Full Text
  73. ↵
    Hosono M, Hosono MN, Kraeber-Bodere F, et al. Biodistribution and dosimetric study in medullary thyroid cancer xenograft using bispecific antibody and iodine-125-labeled bivalent hapten. J Nucl Med. 1998; 39: 1608–1613.
    OpenUrlAbstract/FREE Full Text
  74. ↵
    Gestin JF, Loussouarn A, Bardies M, et al. Two-step targeting of xenografted colon carcinoma using a bispecific antibody and 188Re-labeled bivalent hapten: biodistribution and dosimetry studies. J Nucl Med. 2001; 42: 146–153.
    OpenUrlAbstract/FREE Full Text
  75. ↵
    Karacay H, McBride WJ, Griffiths GL, et al. Experimental pretargeting studies of cancer with a humanized anti-CEA x murine anti-[In-DTPA] bispecific antibody construct and a (99m)Tc-/(188)Re-labeled peptide. Bioconjug Chem. 2000; 11: 842–854.
    OpenUrlCrossRefPubMed
  76. ↵
    Chetanneau A, Barbet J, Peltier P, et al. Pretargetted imaging of colorectal cancer recurrences using an 111In-labelled bivalent hapten and a bispecific antibody conjugate. Nucl Med Commun. 1994; 15: 972–980.
    OpenUrlPubMed
  77. ↵
    Vuillez JP, Moro D, Brichon PY, et al. Two-step immunoscintigraphy for non-small-cell lung cancer staging using a bispecific anti-CEA/anti-indium-DTPA antibody and an indium-111-labeled DTPA dimer. J Nucl Med. 1997; 38: 507–511.
    OpenUrlAbstract/FREE Full Text
  78. ↵
    Peltier P, Curtet C, Chatal JF, et al. Radioimmunodetection of medullary thyroid cancer using a bispecific anti-CEA/anti-indium-DTPA antibody and an indium-111-labeled DTPA dimer. J Nucl Med. 1993; 34: 1267–1273.
    OpenUrlAbstract/FREE Full Text
  79. ↵
    Barbet J, Peltier P, Bardet S, et al. Radioimmunodetection of medullary thyroid carcinoma using indium-111 bivalent hapten and anti-CEA x anti-DTPA-indium bispecific antibody. J Nucl Med. 1998; 39: 1172–1178.
    OpenUrlAbstract/FREE Full Text
  80. ↵
    Bardies M, Bardet S, Faivre-Chauvet A, et al. Bispecific antibody and iodine-131-labeled bivalent hapten dosimetry in patients with medullary thyroid or small-cell lung cancer. J Nucl Med. 1996; 37: 1853–1859.
    OpenUrlAbstract/FREE Full Text
  81. ↵
    Kraeber-Bodere F, Bardet S, Hoefnagel CA, et al. Radioimmunotherapy in medullary thyroid cancer using bispecific antibody and iodine 131-labeled bivalent hapten: preliminary results of a phase I/II clinical trial. Clin Cancer Res. 1999; 5: 3190s–3198s.
    OpenUrlAbstract/FREE Full Text
  82. ↵
    Gruaz-Guyon A, Janevik-Ivanovska E, Raguin O, Labriolle-Vaylet C, Barbet J. Radiolabeled bivalent haptens for tumor immunodetection and radioimmunotherapy. Q J Nucl Med. 2001; 45: 201–206.
    OpenUrlPubMed
  83. ↵
    Schuhmacher J, Klivenyi G, Kaul S, et al. Pretargeting of human mammary carcinoma xenografts with bispecific anti-MUC1/anti-Ga chelate antibodies and immunoscintigraphy with PET. Nucl Med Biol. 2001; 28: 821–828.
    OpenUrlCrossRefPubMed
  84. ↵
    Schuhmacher J, Kaul S, Klivenyi G, et al. Immunoscintigraphy with positron emission tomography: gallium-68 chelate imaging of breast cancer pretargeted with bispecific anti-MUC1/anti-Ga chelate antibodies. Cancer Res. 2001; 61: 3712–3717.
    OpenUrlAbstract/FREE Full Text
  85. ↵
    Zoller M, Schuhmacher J, Reed J, Maier-Borst W, Matzku S. Establishment and characterization of monoclonal antibodies against an octahedral gallium chelate suitable for immunoscintigraphy with PET. J Nucl Med. 1992; 33: 1366–1372.
    OpenUrlAbstract/FREE Full Text
  86. ↵
    Klivenyi G, Schuhmacher J, Patzelt E, et al. Gallium-68 chelate imaging of human colon carcinoma xenografts pretargeted with bispecific anti-CD44V6/anti-gallium chelate antibodies [see comments]. J Nucl Med. 1998; 39: 1769–1776.
    OpenUrlAbstract/FREE Full Text
  87. ↵
    Somasundaram C, Matzku S, Schuhmacher J, Zoller M. Development of a bispecific monoclonal antibody against a gallium-67 chelate and the human melanoma-associated antigen p97 for potential use in pretargeted immunoscintigraphy. Cancer Immunol Immunother. 1993; 36: 337–345.
    OpenUrlPubMed
  88. ↵
    Schuhmacher J, Klivenyi G, Matys R, et al. Multistep tumor targeting in nude mice using bispecific antibodies and a gallium chelate suitable for immunoscintigraphy with positron emission tomography. Cancer Res. 1995; 55: 115–123.
    OpenUrlAbstract/FREE Full Text
PreviousNext
Back to top

In this issue

Journal of Nuclear Medicine
Vol. 44, Issue 3
March 1, 2003
  • Table of Contents
  • Index by author
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word on Journal of Nuclear Medicine.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Pretargeted Radioimmunotherapy of Cancer: Progress Step by Step
(Your Name) has sent you a message from Journal of Nuclear Medicine
(Your Name) thought you would like to see the Journal of Nuclear Medicine web site.
Citation Tools
Pretargeted Radioimmunotherapy of Cancer: Progress Step by Step
Otto C. Boerman, Frank G. van Schaijk, Wim J.G. Oyen, Frans H.M. Corstens
Journal of Nuclear Medicine Mar 2003, 44 (3) 400-411;

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Pretargeted Radioimmunotherapy of Cancer: Progress Step by Step
Otto C. Boerman, Frank G. van Schaijk, Wim J.G. Oyen, Frans H.M. Corstens
Journal of Nuclear Medicine Mar 2003, 44 (3) 400-411;
Twitter logo Facebook logo LinkedIn logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One
Bookmark this article

Jump to section

  • Article
    • Abstract
    • THE CONCEPT OF PRETARGETING
    • PRETARGETING BASED ON BIOTIN AND AVIDIN
    • THE MILAN EXPERIENCE
    • THE NeoRx APPROACH
    • THE ROLE OF ENDOGENOUS BIOTIN AND BIOTINIDASE
    • PRETARGETING WITH BISPECIFIC mAbs (bsmAbs)
    • bsmAb-BASED PRETARGETED RADIOIMMUNOTHERAPY IN PATIENTS
    • PRETARGETED PET IMAGING
    • CONCLUSION
    • Acknowledgments
    • Footnotes
    • REFERENCES
  • Figures & Data
  • Info & Metrics
  • PDF

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Cited By...

  • A Pretargeted PET Imaging Strategy Based on Bioorthogonal Diels-Alder Click Chemistry
  • Effect of Small-Molecule-Binding Affinity on Tumor Uptake In Vivo: A Systematic Study Using a Pretargeted Bispecific Antibody
  • 124I-huA33 Antibody Uptake Is Driven by A33 Antigen Concentration in Tissues from Colorectal Cancer Patients Imaged by Immuno-PET
  • Pretargeted 177Lu Radioimmunotherapy of Carcinoembryonic Antigen-Expressing Human Colonic Tumors in Mice
  • Pretargeted Immuno-Positron Emission Tomography Imaging of Carcinoembryonic Antigen-Expressing Tumors with a Bispecific Antibody and a 68Ga- and 18F-Labeled Hapten Peptide in Mice with Human Tumor Xenografts
  • A comparative analysis of conventional and pretargeted radioimmunotherapy of B-cell lymphomas by targeting CD20, CD22, and HLA-DR singly and in combinations
  • Introduction to the Eleventh Conference on Cancer Therapy with Antibodies and Immunoconjugates
  • Optimization of Radioimmunotherapy of Solid Tumors: Biological Impediments and Their Modulation
  • Bispecific Antibody Pretargeting of Tumor Neovasculature for Improved Systemic Radiotherapy of Solid Tumors
  • Successful Radiotherapy of Tumor in Pretargeted Mice by 188Re-Radiolabeled Phosphorodiamidate Morpholino Oligomer, a Synthetic DNA Analogue.
  • Antibody Pretargeting Advances Cancer Radioimmunodetection and Radioimmunotherapy
  • Targeting, Toxicity, and Efficacy of 2-Step, Pretargeted Radioimmunotherapy Using a Chimeric Bispecific Antibody and 131I-Labeled Bivalent Hapten in a Phase I Optimization Clinical Trial
  • Radioimmunotherapy of Solid Tumors: The Promise of Pretargeting Strategies Using Bispecific Antibodies and Radiolabeled Haptens
  • Pretargeted Radioimmunotherapy with a Single-Chain Antibody/Streptavidin Construct and Radiolabeled DOTA-Biotin: Strategies for Reduction of the Renal Dose
  • Intraperitoneal Pretarget Radioimmunotherapy with CC49 Fusion Protein
  • Therapeutic Advantage of Pretargeted Radioimmunotherapy Using a Recombinant Bispecific Antibody in a Human Colon Cancer Xenograft
  • Enhanced Efficacy of Radioimmunotherapy with 90Y-CHX-A''-DTPA-hu3S193 by Inhibition of Epidermal Growth Factor Receptor (EGFR) Signaling with EGFR Tyrosine Kinase Inhibitor AG1478
  • Introduction to the Tenth Conference on Cancer Therapy with Antibodies and Immunoconjugates
  • Improving the Delivery of Radionuclides for Imaging and Therapy of Cancer Using Pretargeting Methods
  • Radioimmunotherapy of Prostate Cancer: Does Tumor Size Matter?
  • Residualizing Iodine Markedly Improved Tumor Targeting Using Bispecific Antibody-Based Pretargeting
  • Novel Avidin-like Protein from a Root Nodule Symbiotic Bacterium, Bradyrhizobium japonicum
  • The Direct Route May Not Be the Best Way to Home
  • Perspectives on Cancer Therapy with Radiolabeled Monoclonal Antibodies
  • Pretargeting with Labeled Bivalent Peptides Allowing the Use of Four Radionuclides: 111In, 131I, 99mTc, and 188Re
  • Google Scholar

More in this TOC Section

  • From Concept to Regulatory Drug Approval: Lessons for Theranostics
  • Oligometastatic Prostate Cancer: Current Status and Future Challenges
  • Dosimetry in Radiopharmaceutical Therapy
Show more Continuing Education

Similar Articles

SNMMI

© 2023 Journal of Nuclear Medicine

Powered by HighWire