Study of radiolabeled indium-111 and yttrium-90 ibritumomab tiuxetan in primary central nervous system lymphoma

BACKGROUND: Therapeutic options for refractory or recurrent primary central nervous system lymphoma (PCNSL) are limited. The blood-brain barrier makes many agents used in systemic lymphomas ineffective in CNS lymphomas. The objective of this study was to determine whether intravenous radioimmunotherapy using anti-CD20 antibody can be delivered to PCNSL. METHODS: This was a single-institution prospective study. Indium-111 ibritumomab tiuxetan was used for imaging and dosimetry. Yttrium-90 ibritumomab tiuxetan at doses of 0.3 to 0.4 mCi/kg were subsequently given for the treatment of recurrent or refractory PCNSL. 111In data were used to estimate radiation doses to lesions delivered by 90Y ibritumomab tiuxetan therapy. RESULTS: Six patients (4 men, 2 women) with a median age of 60 years and median Karnofsky performance status of 70 received both indium-111 and yttrium-90 ibritumomab tiuxetan. The median absorbed dose delivered to the CNS lymphoma was 701 cGy compared with 70 cGy to normal brain. The median progression-free and overall survival times were 6.8 weeks and 14.3 weeks, respectively. CONCLUSIONS: The results from this study suggest that it may be feasible to deliver radiolabeled monoclonal anti-CD20 antibodies as a component of therapy for PCNSL.     

Automated module radiolabeling of peptides and antibodies with gallium-68, lutetium-177 and iodine-131

Our objectives were to automate radiolabeling of therapeutic activities for safe, reliable, cost-effective, practical routine preparation of (177)Lu-radiopeptides, (131)I radioimmunotherapeutic agents, and (68)Ga-peptide PET diagnostics and, in particular, minimize radiation exposure to the radiopharmaceutical chemist. Reprogramming and adaptation of a commercially available synthetic module (IBA molecular; Synthera?) allowed high yield, fully automated, in-house radiolabeling of novel therapeutic and diagnostic radiopharmaceuticals under remote shielded sterile conditions. Radiochemical yield and purity was measured by instant thin-layer chromatography and high-performance liquid chromatography. (68)Ga-octreotate and (177)Lu-octreotate were synthesized, resulting in both radiochemical yield and radiochemical purity greater than 99%. Synthesis of (131)I-rituximab resulted in a yield of 60%, with a radiochemical purity greater than 99%. Using 400?MBq (68)GaCl(3) per synthesis, the estimated absorbed body and hand dose for a manual synthesis was 2 and 27?μ Sv, contrasting with automated synthesis exposure of 1.3 and 7.9?μ Sv. Using 8000?MBq (177)LuCl(3) per synthesis, the estimated absorbed body and hand dose for a manual synthesis was 44.7 and 75?μ Sv, contrasting with automated synthesis exposure of 2.5 and 20?μ Sv. Using 6000?MBq (131)I per synthesis, the estimated absorbed body and hand dose for a manual synthesis was 83.7 and 335?μ Sv, contrasting with automated synthesis exposure of 10.9 and 54.7?μ Sv. The reduction in radiation exposure by automated synthesis of radiopharmaceuticals in the Synthera? module was at least five fold. Automated synthesis of therapeutic (177)Lu and (131)I radiopharmaceuticals and (68)Ga PET agents in the shielded sterile Synthera? module is simple, practical, and efficient and virtually eliminates radiation exposure to the radiopharmaceutical chemist.     

Preparation and properties of antitumor monoclonal antibodies labeled with metallic radionuclides indium-111, gallium-67, and technetium-99m

In this study, metallic radionuclides such as 111In, 67Ga, or 99mTc produced clear visualization in scintigraphic imaging of tumors; they have short half-lives and can easily be used in the radiolabeling of monoclonal antibodies by using bifunctional chelating agents. Under selected conditions, these radiolabeled antibodies were stable both in vitro and in vivo with no loss of the antigen-binding activity. Despite high background imaging of the liver and kidney, transplanted tumors in nude mice were clearly visualized with 111In-, 67Ga-, and 99mTc-labeled antibodies at 6, 24, or 48 hours after the injection. Although tissue distribution in the liver, kidney, and bone was different among radionuclides used for the labeling, all tumor to blood ratios were higher than those of radioiodinated monoclonal antibodies. These results provide a good basis for studies of the clinical usefulness of 111In-, 67Ga-, and 99mTc-labeled monoclonal antibodies for radioimmunoimaging.     

Intratumoral consumption of indium-111 labeled platelets in a patient with hemangiomatosis and intravascular coagulation (Kasabach-Merritt syndrome)

Previous studies regarding sites of platelet destruction in patients with the Kasabach-Merritt syndrome are conflicting. The authors recently studied an adult patient with multiple large hemangiomata, thrombocytopenia, and intravascular coagulation by external imaging following the injection of autologous Indium-111 labeled platelets. Sequential images showed prompt accumulation of platelet-associated radioactivity in areas within the right hemithorax which corresponded to certain tumors noted on the chest roentgenogram. Despite the presence of multiple other lesions in bone and soft tissues, platelet radioactivity was otherwise normally confined to liver and spleen. Using data obtained from serial images, it was shown that radioactivity within the thoracic masses actually increased over time. These data indicate that platelet consumption occurred as an active process and that localization was not a result of tumor vascularity. It is concluded that platelets are locally consumed within certain hemangiomata. However, within the same individual, there may exist considerable heterogeneity among these tumors with respect to platelet-trapping ability. In similar patients with multiple tumors, indium-platelet scanning might be used to direct local therapy to particular lesions in an effort to correct the thrombocytopenia.     

Radiotherapy of CD45-expressing Daudi tumors in nude mice with yttrium-90-labeled, PEGylated anti-CD45 antibody

Studies were performed to determine the suitability of using the polyethylene glycol (PEG)-labeled AHN-12 anti-CD45 monoclonal antibody to deliver the high-energy beta-particle-emitting isotope 90Y to a CD45+ B-cell Daudi lymphoma grown as flank tumors in athymic nude mice. The PEGylated radiolabeled antibody displayed a significantly better antitumor effect in the mouse tumor flank model (p<0.03) and significantly better blood pharmacokinetics in normal rats (p<0.05) than the non-PEGylated radiolabeled antibody. Studies of two different sizes of PEG showed that rats given 43 kDa of PEGylated AHN-12, but not 5 kDa of PEGylated AHN-12, had significantly higher radiolabeled antibody blood levels and, therefore, improved pharmacokinetics, as compared to rodents given non-PEGylated radiolabeled AHN-12 (p<0.05). Surviving mice revealed no signs of kidney, liver, or gastrointestinal damage by histology study. Notably, in vitro studies indicated that PEGylation did not have a major effect on labeling efficiency and the binding of labeled antibody. These findings indicate that PEGylation of radiolabeled anti-CD45 antibody may be a useful and desirable means of extending blood half-life and enhancing efficacy. Also, the final outcome may be impacted by the size of the PEG molecule used for the modification of the blood half-life.     

Tumor targeting properties of indium-111 labeled genetically engineered Fab' and F(ab')2 constructs of chimeric tumor necrosis treatment (chTNT)-3 antibody

Genetic engineering techniques have allowed the construction of Fab' and F(ab')2 constructs of chimeric tumor necrosis treatment antibody (chTNT-3), a chimeric monoclonal antibody (MAb) that targets necrotic regions of solid tumors. The purpose of this study is to evaluate the in vitro and in vivo properties of Fab' and F(ab')2 constructs radiolabeled with indium-111 (111In) using diethylentriamine pentaacetic acid (DTPA) conjugation to develop a clinically useful imaging agent for the detection of necrosis in solid tumors. Optimization of the MAb-to-DTPA ratio showed that a 1:2 ratio gave the best immunoreactivity while providing good radiolabeling efficiency and high specific activity for all three DPTA conjugates. In addition, 111In-labeled Fab' and F(ab')2 conjugates were found to have faster whole body clearance times and better biodistribution profiles compared to parental 111In-labeled chTNT-3 in tumor-bearing mice. Although radiolabeled Fab' and F(ab')2 constructs showed lower tumor uptake than radiolabeled chTNT-3, biodistribution results showed that these constructs had significantly lower uptake in liver, spleen, and other normal organs (except the kidney), and therefore had higher tumor-to-organ ratios. In addition, a comparison of all derivatives showed that the F(ab')2 reagent gave the best results in tumor imaging studies. These results demonstrate that stable, a genetically engineered F(ab')2 construct can be successfully radiolabeled with 111In to produce potential imaging reagents for the imaging and monitoring of tumor necrosis.     

High-dose radioimmunotherapy combined with fixed, low-dose paclitaxel in metastatic prostate and breast cancer by using a MUC-1 monoclonal antibody, m170, linked to indium-111/yttrium-90 via a cathepsin cleavable linker with cyclosporine to prevent human anti-mouse antibody.

PURPOSE: Although radioimmunotherapy alone is effective in lymphoma, its application to solid tumors will likely require a combined modality approach. In these phase I studies, paclitaxel was combined with radioimmunotherapy in patients with metastatic hormone-refractory prostate cancer or advanced breast cancer. EXPERIMENTAL DESIGN: Patients were imaged with indium-111 (111In)-1,4,7,10-tetraazacyclododecane-N,N',N',N'-tetraacetic acid-peptide-m170. One week later, yttrium-90 (90Y)-m170 was infused (12 mCi/m2 for prostate cancer and 22 mCi/m2 for breast cancer). Initial cohorts received radioimmunotherapy alone. Subsequent cohorts received radioimmunotherapy followed 48 hours later by paclitaxel (75 mg/m2). Cyclosporine was given to prevent development of human anti-mouse antibody. RESULTS: Bone and soft tissue metastases were targeted by 111In-m170 in 15 of the 16 patients imaged. Three prostate cancer patients treated with radioimmunotherapy alone had no grade 3 or 4 toxicity. With radioimmunotherapy and paclitaxel, two of three prostate cancer patients developed transient grade 4 neutropenia. Four breast cancer patients treated with radioimmunotherapy alone had grade 3 or 4 myelosuppression. With radioimmunotherapy and paclitaxel, both breast cancer patients developed grade 4 neutropenia. Three breast cancer patients required infusion of previously harvested peripheral blood stem cells because of neutropenic fever or bleeding. One patient in this trial developed human anti-mouse antibody in contrast to 12 of 17 patients in a prior trial using m170-radioimmunotherapy without cyclosporine. CONCLUSIONS: 111In/90Y-m170 targets prostate and breast cancer and can be combined with paclitaxel with toxicity limited to marrow suppression at the dose levels above. The maximum tolerated dose of radioimmunotherapy and fixed-dose paclitaxel with peripheral blood stem cell support has not been reached. Cyclosporine is effective in preventing human anti-mouse antibody, suggesting the feasibility of multidose, "fractionated" therapy that could enhance clinical response.     

大鼠中确定90Y 或177Lu标定的单克隆抗体BR96的最大耐受剂量——-同源性肿瘤模型的建立

 目的　比较90Y和177Lu标记的单克隆抗体BR96在正常大鼠体内的最大耐受剂量（MTD）。方法　将动物分组,分别注射不同剂量的90Y-BR96以及177Lu-BR96。观测8周内血象、体质量以及生命指征变化。结果　注射2 d后所有组大鼠白细胞均下降至开始的5 %～15 %;注射后第14天至第21天开始恢复并呈剂量依赖性。除90Y-BR96的最高剂量组外,其余各组大鼠白细胞均完全恢复。在注射后第7天至第14天血小板开始减少,其严重程度（至开始的10 %～40 %）和开始恢复的时间与注射剂量有关。注射后第21天在90Y-BR96以及177Lu-BR96最高剂量组中发现有皮肤感染。结论　大鼠对90Y-BR96和177Lu-BR96的毒性均呈剂量依赖性。177Lu-BR96的MTD（1000 MBq／kg）是90Y-BR96的1.7倍,在该组中可注射较高剂量的螯合物而正常组织不受损。该实验重复性好,该模型可用来评估一些提高肿瘤增益比的新方法,如放射免疫靶向治疗等。     

The in vivo distribution of indium-111 labeled in vitro alloactivated syngeneic lymphocytes in a patient with relapsed acute myelomonocytic leukemia: implications for adoptive chemoimmunotherapy

A single patient who had a leukemic relapse six months after receiving a syngeneic bone marrow transplant was given "adoptive chemoimmunotherapy." Lymphocytes from the patients identical twin were alloactivated and grown in T cell growth factor in vitro. After receiving chemotherapy to reduce the number of relapsed leukemia cells, he received 1.1 X 10(10) in vitro alloactivated twin lymphocytes via intravenous and intraperitoneal injections. Although progressive Candidal pneumonia was fatal and prevented analysis of either efficacy or delayed toxicity of this potential form of therapy for this patient, radioactive 111In labelling and scanning showed dissemination of these lymphocytes following either injection route, with no clinical evidence of immediate toxicity.     

Carcinoembryonic antigen as a target for radioimmunotherapy of human medullary thyroid carcinoma: antibody processing, targeting, and experimental therapy with 131I and 90Y labeled MAbs

The poor prognosis of patients with advanced medullary thyroid carcinoma (MTC) has prompted a search for new treatment modalities. In this report we explore the characteristics of carcinoembyronic antigen (CEA) as a target for radioimmunotherapy (RAIT) of MTC, with respect to antibody processing, targeting, and experimental therapy. In vitro studies showed a high level of CEA expression on the cell surface of the MTC cell line TT. MAbs bound to the cell were predominantly retained for several days, although there was also a significant level of internalization and catabolism. Immunohistology of frozen sections of tumor xenografts demonstrated that approximately half of the cells were darkly stained, however, some cells expressed little or no CEA. In biodistribution studies in nude mice bearing TT tumors, the mean percent injected dose per gram of tumor observed at three days post injection (time of maximum uptake) of 125I-MN-14 was 19.7%. When the MAb was labeled with 88Y, a residualizing label, a much higher accretion, 50.5%, was observed at the time of maximum uptake (7 days). Significant anti-tumor effects were seen at the maximum tolerated doses of 131I- and 90Y-MN-14, compared with relatively rapid tumor growth in untreated animals or those treated with the same dose of control MAbs. Importantly, it was observed that 90Y-MN-14 yielded significantly improved therapeutic efficacy in comparison to 131I-MN-14, which may have important implications for design and conduct of future clinical trials for the treatment of MTC.     

Effect of yttrium-90-labeled anti-carcinoembryonic antigen monoclonal antibody on the morphology and phenotype of human tumors grown as peritoneal carcinomatosis in athymic mice

Grossly visible peritoneal carcinomatosis resembling that seen in man was produced in athymic mice 7 days after intraperitoneal injection of 8 x 10(5) cells of the carcinoembryonic antigen (CEA)-producing human colon carcinoma cell line LS174T. The mice received intraperitoneal injections of 40 to 160 microCi of yttrium-90 (90Y)-labeled anti-CEA monoclonal antibody (MAb). When the mice were killed 12 days after injection, a significant inhibition of tumor growth, ranging from 40% to 95%, was observed in the treated animals when compared to the growth of tumors in the untreated animals (P less than 0.001). No mortality secondary to the therapy was seen. The bone marrow was depleted significantly at the higher doses of labeled MAb, but total recovery was observed 4 weeks after treatment. Histologically, the treated tumors showed extensive radiation effects early in the posttherapy period and massive necrosis at later times. Minute foci of viable tumor remained in the periphery. New tumor outgrowths with histologic features similar to those in the untreated controls began to appear 3 weeks after therapy. The CEA expression of the treated tumors was similar to that of the untreated controls during the early posttreatment period, diminishing progressively as the tumors became necrotic. Newly grown tumor nodules in the treated animals lacked significant CEA expression both initially and at later times. Our studies suggest that therapy with 90Y-anti-CEA MAb therapy results in selection of tumor clones lacking CEA, and that a single large dose of 90Y-MAb should be more effective than multiple fractions of smaller doses.     

Comparative physical and pharmacologic characteristics of iodine-131 and yttrium-90: implications for radioimmunotherapy for patients with non-Hodgkin's lymphoma

Radioimmunotherapy (RIT) is a promising new treatment option for patients with relapsed/refractory non-Hodgkin's lymphoma. Clinical trials have demonstrated that both iodine-131 (¹³¹I) and yttrium-90 (⁹⁰Y) are suitable radionuclides for RIT. Iodine-131 and ⁹⁰Y differ markedly in their physical properties including half-life, path length, type of energy emissions, intracellular stability, and the organs targeted by the free radionuclide. Both radionuclides can be safely administered in the outpatient setting under current Nuclear Regulatory Commission guidelines. Potential advantages of ¹³¹I for RIT include availability, stable chemistry, longer half-life, and an emission spectrum that allows for dosimetric studies and therapy with the same immunoconjugate. By contrast, ⁹⁰Y has a longer path length and superior intracellular stability compared with ¹³¹I. Yttrium-90 may therefore be preferable to ¹³¹I for patients with bulky disease, poorly vascularized solid tumors, or when targeting internalized antigens. Although ⁹⁰Y emits no gamma photon, dosimetry studies for ⁹⁰Y RIT can be performed using a surrogate radionuclide such as indium-111. Both ¹³¹I- and ⁹⁰Y-labeled anti-CD20 antibodies have demonstrated efficacy in treating relapsed/refractory non-Hodgkin's lymphoma. Further studies are needed, however, to determine if the differences in the pharmacology of ¹³¹I and ⁹⁰Y are clinically relevant.     

Pre-clinical evaluation of [(111)In-DTPA-Pro(1), Tyr(4)]bombesin, a new radioligand for bombesin-receptor scintigraphy.

Bombesin (BN) is a 14-amino-acid neuropeptide with a high affinity for the gastrin-releasing peptide receptor. This receptor has been found to be expressed in a variety of tumours, including lung, breast, prostate and pancreas. A newly synthesized BN analogue, [DTPA-Pro(1),Tyr(4)]BN, was shown to be a high-affinity BN-receptor (BNR) agonist, stimulating prolactin secretion from 7315b cells with an IC(50) of 8 nM. The (111)In-labelled analogue was found to bind with high affinity to rat BNR in vitro and in vivo. The radioligand is internalized by BNR-expressing cells, in contrast to DTPA-conjugated BN antagonists. Therefore, we further studied the biodistribution of i.v. injected [(111)In-DTPA-Pro(1),Tyr(4)]BN in rats. High and specific uptake was found in tissues of the gastrointestinal tract, notably pancreas. Uptake of radioactivity was blocked by pre- or co-injection of 100 microgram [Tyr(4)]BN, but not when this was administered 30 min after the radioligand. This suggests BNR-mediated internalization of the radioligand within 30 min. The percentage injected dose (ID) taken up by BNR-positive tissues was a bell-shaped function of the amount (0.01-0.1 microgram) of injected ligand. Next to the pancreas, highest uptake was observed in the kidneys, which was not blocked by excess [Tyr(4)]BN. Dynamic gamma camera studies showed rapid clearance of radioactivity from the blood compartment. Urinary excretion amounted to about 35% ID after 1 hr and to 70% ID after 24 hr, with a total body retention of 10% ID. Specific uptake was found in the BNR-positive CA20948 pancreas tumour and CC531 colon carcinoma in tumour-bearing rats. The CA20948 tumour, inoculated in the hindleg, was also visualized scintigraphically. [(111)In-DTPA-Pro(1), Tyr(4)]BN appears to be a promising radioligand for scintigraphy of BNR-expressing tumours.     

In vitro and in vivo characterization of Indium-111 and Technetium-99m labeled CCK-8 derivatives for CCK-B receptor imaging

Cholecystokinin (CCK) receptors of the subtype B (CCK-BR) have been shown to be overexpressed in certain neuroendocrine tumors including medullary thyroid cancer. Our recent work has focused on new methods to radiolabel the CCK8 peptide with 111In or 99mTc for CCK-B receptor imaging. Derivatives of CCK8 were obtained by addition at the N-terminus in solid phase of a DTPA derivative (DTPAGlu) linked through a glycine spacer (DTPAGlu-G-CCK8) or cysteine, glycine and a diphenylphosphinopropionyl moiety (PhosGC-CCK8) for labeling with 111In and 99mTc, respectively. CCK-BR overexpressing A431 cancer cell lines were utilized to characterize in vitro properties of the two compounds as well as for generating xenografts in nude mice for in vivo characterization. Both 111In-DTPAGlu-G-CCK8 and 99mTcPhosGC-CCK8 showed similar binding affinities for CCK-BR with dissociation constants of 20-40 nM, were internalized after interaction with the receptor and displayed prolonged cellular retention times. Specific in vivo interaction with the receptor of both CCK8 analogs was observed in our animal model. 111In-DTPAGlu-G-CCK8 showed better target to non-target ratios, although it appeared to be rapidly metabolized after injection and activity cleared through the kidneys. 99mTc-PhosGC-CCK8 was more stable in vivo but showed marked hepatobiliary clearance with resulting high background activity in the bowel. The rapid clearance and lower background obtained with 111In-DTPAGlu-G-CCK8 make this a better candidate for further development.     

Computational modeling and experimental evaluation of a novel prodrug for targeting the extracellular space of prostate tumors

We are developing a noninvasive approach for targeting imaging and therapeutic radionuclides to prostate cancer. Our method, Enzyme-Mediated Cancer Imaging and Therapy (EMCIT), aims to use enzyme-dependent, site-specific, in vivo precipitation of a radioactive molecule within the extracellular space of solid tumors. Advanced methods for data mining of the literature, protein databases, and knowledge bases (IT.Omics LSGraph and Ingenuity Systems) identified prostatic acid phosphatase (PAP) as an enzyme overexpressed in prostate cancer and secreted in the extracellular space. Using AutoDock 3.0 software, the prodrug ammonium 2-(2'-phosphoryloxyphenyl)-6-iodo-4-(3H)-quinazolinone (IQ(2-P)) was docked in silico into the X-ray structure of PAP. The data indicate that IQ(2-P) docked into the PAP active site with a calculated inhibition constant (K(i)) more favorable than that of the PAP inhibitor alpha-benzylaminobenzylphosphonic acid. When (125)IQ(2-P), the radioiodinated form of the water-soluble prodrug, was incubated with PAP, rapid hydrolysis of the compound was observed as exemplified by formation of the water-insoluble 2-(2'-hydroxyphenyl)-6-[(125)I]iodo-4-(3H)-quinazolinone ((125)IQ(2-OH)). Similarly, the incubation of IQ(2-P) with human LNCaP, PC-3, and 22Rv1 prostate tumor cells resulted in the formation of large fluorescent IQ(2-OH) crystals. No hydrolysis was seen in the presence of normal human cells. Autoradiography of tumor cells incubated with (125)IQ(2-P) showed accumulation of radioactive grains ((125)IQ(2-OH)) around the cells. We anticipate that the EMCIT approach will enable the active in vivo entrapment of radioimaging and radiotherapeutic compounds within the extracellular spaces of primary prostate tumors and their metastases.     

A phase 2 trial of fludarabine and mitoxantrone chemotherapy followed by yttrium-90 ibritumomab tiuxetan for patients with previously untreated, indolent, nonfollicular, non-Hodgkin lymphoma

BACKGROUND: A prospective, single-arm, open-label, nonrandomized Phase 2 study of combined fludarabine and mitoxantrone (FM) plus radioimmunotherapy was conducted to evaluate efficacy and safety in patients with untreated, indolent, nonfollicular non-Hodgkin lymphoma (NHL). METHODS: Between February 2005 and June 2006, at their institute, the authors treated 26 eligible patients with previously untreated, indolent, nonfollicular NHL (10 marginal zone lymphomas, 8 lymphoplasmacytic lymphomas, and 8 small lymphocytic lymphomas) using a novel regimen that consisted of 6 cycles of FM chemotherapy followed 6 to 10 weeks later by yttrium-90 (90Y) ibritumomab tiuxetan. RESULTS: After FM chemotherapy, the overall response rate was 80.5% and included a 50% complete remission (CR) rate (13 patients) and a 30.5% partial remission (PR) rate (8 patients). Of the 20 patients (13 with CR and 7 with PR) who were evaluable (at least a PR with normal platelet counts and bone marrow infiltration <25%) for subsequent 90Y ibritumomab tiuxetan, 100% obtained a CR at the end of the entire treatment regimen. At a median follow-up of 20 months, the estimated 3-year progression-free survival rate was 89.5%, and the estimated 3-year overall survival rate was 100%. The 90Y ibritumomab tiuxetan toxicity included grade >or=3 hematologic toxicity in 16 of 20 patients; the most common grade >or=3 toxicities were neutropenia (11 patients) and thrombocytopenia (16 patients) (adverse events were graded according to the World Health Organization criteria for toxicity). Transfusions of erythrocytes and/or platelets were given to 5 patients. CONCLUSIONS: The current study established the feasibility, tolerability, and efficacy of the FM plus 90Y ibritumomab tiuxetan regimen for the treatment of patients with untreated, indolent, nonfollicular NHL.     

Therapeutic efficacy evaluation of radioimmunotherapy with 90Y‐labeled anti‐podoplanin antibody NZ‐12 for mesothelioma

Podoplanin is a type I transmembrane sialomucin‐like glycoprotein that is highly expressed in malignant mesothelioma. The rat‐human chimeric antibody NZ‐12 has high affinity for human podoplanin and antibody‐dependent cellular cytotoxicity and is applicable for radioimmunotherapy (RIT) to enhance the antitumor effect. In the present study, we evaluated the in vivo and in vitro properties of radiolabeled NZ‐12 and the antitumor effect of RIT with ⁹⁰Y‐labeled NZ‐12 in an NCI‐H226 (H226) malignant mesothelioma xenograft mouse model. ¹¹¹In‐labeled NZ‐12 bound specifically to H226 cells with high affinity, and accumulation was high in H226 tumors but low in major organs. RIT with ⁹⁰Y‐labeled NZ‐12 significantly suppressed tumor growth and prolonged survival without body weight loss and obvious adverse effects. Higher podoplanin expression levels were observed in human mesothelioma specimens, suggesting higher tumor accumulation of ⁹⁰Y‐labeled NZ‐12 in patients compared with the H226 tumor xenografts. Our findings suggest that ⁹⁰Y‐labeled NZ‐12 is a promising RIT agent as a new therapeutic option for malignant mesothelioma that warrants further clinical studies to evaluate the dosimetry and efficacy in patients.