Long-Term Toxicity of 213Bi-Labelled BSA in Mice

Background

Short-term toxicological evaluations of alpha-radioimmunotherapy have been reported in preclinical assays, particularly using bismuth-213 (²¹³Bi). Toxicity is greatly influenced not only by the pharmacokinetics and binding specificity of the vector but also by non-specific irradiation due to the circulating radiopharmaceutical in the blood. To assess this, an acute and chronic toxicity study was carried out in mice injected with ²¹³Bi-labelled Bovine Serum Albumin (²¹³Bi-BSA) as an example of a long-term circulating vector.

Method

Biodistribution of ²¹³Bi-BSA and ¹²⁵I-BSA were compared in order to evaluate ²¹³Bi uptake by healthy organs. The doses to organs for injected ²¹³Bi-BSA were calculated. Groups of nude mice were injected with 3.7, 7.4 and 11.1 MBq of ²¹³Bi-BSA and monitored for 385 days. Plasma parameters, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN) and creatinine, were measured and blood cell counts (white blood cells, platelets and red blood cells) were performed. Mouse organs were examined histologically at different time points.

Results

Haematological toxicity was transient and non-limiting for all evaluated injected activities. At the highest injected activity (11.1 MBq), mice died from liver and kidney failure (median survival of 189 days). This liver toxicity was identified by an increase in both ALT and AST and by histological examination. Mice injected with 7.4 MBq of ²¹³Bi-BSA (median survival of 324 days) had an increase in plasma BUN and creatinine due to impaired kidney function, confirmed by histological examination. Injection of 3.7 MBq of ²¹³Bi-BSA was safe, with no plasma enzyme modifications or histological abnormalities.

Conclusion

Haematological toxicity was not limiting in this study. Liver failure was observed at the highest injected activity (11.1 MBq), consistent with liver damage observed in human clinical trials. Intermediate injected activity (7.4 MBq) should be used with caution because of the risk of long-term toxicity to kidneys.     

Comparison between Internalizing Anti-HER2 mAbs and Non-Internalizing Anti-CEA mAbs in Alpha-Radioimmunotherapy of Small Volume Peritoneal Carcinomatosis Using 2 1 2Pb

Background and Purpose

We assessed the contribution of antibody internalization in the efficacy and toxicity of intraperitoneal α-radioimmunotherapy (RIT) of small volume carcinomatosis using ²¹²Pb-labeled monoclonal antibodies (mAbs) that target HER2 (internalizing) or CEA (non-internalizing) receptors.

Materials and Methods

Athymic nude mice bearing 2–3 mm intraperitoneal tumor xenografts were intraperitoneally injected with similar activities (370, 740 and 1480 kBq; 37 MBq/mg) of ²¹²Pb-labeled 35A7 (anti-CEA), trastuzumab (anti-HER2) or PX (non-specific) mAbs, or with equivalent amounts of unlabeled mAbs, or with NaCl. Tumor volume was monitored by bioluminescence and survival was reported. Hematologic toxicity and body weight were assessed. Biodistribution of ²¹²Pb-labeled mAbs and absorbed dose-effect relationships using MIRD formalism were established.

Results

Transient hematological toxicity, as revealed by white blood cells and platelets numbering, was reported in mice treated with the highest activities of ²¹²Pb-labeled mAbs. The median survival (MS) was significantly higher in mice injected with 1.48 MBq of ²¹²Pb-35A7 (non-internalizing mAbs) (MS = 94 days) than in animals treated with the same activity of ²¹²Pb-PX mAbs or with NaCl (MS = 18 days). MS was even not reached after 130 days when follow-up was discontinued in mice treated with 1.48 MBq of ²¹²Pb-trastuzumab. The later efficacy was unexpected since final absorbed dose resulting from injection of 1.48 MBq, was higher for ²¹²Pb-35A7 (35.5 Gy) than for ²¹²Pb-trastuzumab (27.6 Gy). These results also highlight the lack of absorbed dose-effect relationship when mean absorbed dose was calculated using MIRD formalism and the requirement to perform small-scale dosimetry.

Conclusions

These data indicate that it might be an advantage of using internalizing anti-HER2 compared with non-internalizing anti-CEA ²¹²Pb-labeled mAbs in the therapy of small volume xenograft tumors. They support clinical investigations of ²¹²Pb-mAbs RIT as an adjuvant treatment after cytoreductive surgery in patients with peritoneal carcinomatosis.     

Atrophic thyroid follicles and inner ear defects reminiscent of cochlear hypothyroidism in Slc26a4-related deafness

Thyroid hormone is essential for inner ear development and is required for auditory system maturation. Human mutations in SLC26A4 lead to a syndromic form of deafness with enlargement of the thyroid gland (Pendred syndrome) and non-syndromic deafness (DFNB4). We describe mice with an Slc26a4 mutation, Slc26a4 ^loop/loop , which are profoundly deaf but show a normal sized thyroid gland, mimicking non-syndromic clinical signs. Histological analysis of the thyroid gland revealed defective morphology, with a majority of atrophic microfollicles, while measurable thyroid hormone in blood serum was within the normal range. Characterization of the inner ear showed a spectrum of morphological and molecular defects consistent with inner ear pathology, as seen in hypothyroidism or disrupted thyroid hormone action. The pathological inner ear hallmarks included thicker tectorial membrane with reduced β-tectorin protein expression, the absence of BK channel expression of inner hair cells, and reduced inner ear bone calcification. Our study demonstrates that deafness in Slc26a4 ^loop/loop mice correlates with thyroid pathology, postulating that sub-clinical thyroid morphological defects may be present in some DFNB4 individuals with a normal sized thyroid gland. We propose that insufficient availability of thyroid hormone during inner ear development plays an important role in the mechanism underlying deafness as a result of SLC26A4 mutations.     

Testicular Busulfan Injection in Mice to Prepare Recipients for Spermatogonial Stem Cell Transplantation Is Safe and Non-Toxic

Current methods of administering busulfan to remove the endogenous germ cells cause hematopoietic toxicity, require special instruments and a narrow transplantation time. We use a direct testicular injection of busulfan method for preparing recipients for SSC transplantation. Male ICR mice (recipients) were divided into four groups, and two experimental groups were treated with a bilateral testicular injection of 4 or 6 mg/kg/side busulfan (n = 60 per concentration group). Mice received an intraperitoneal injection (i.p.) of 40 mg/kg busulfan (n = 60, positive control) and bilateral testicular injections of 50% DMSO (n = 60, negative control). Donor SSCs from RFP-transgenic C57BL/6J mice were introduced into the seminiferous tubules of each recipient testis via efferent duct injection on day 16–17 after busulfan treatment. Recipient mice mated with mature female ICR mice and the number of progeny was recorded. The index detected at day 14, 21, 28, 35 and 70 after busulfan treatment. Blood analysis shows that the toxicity of busulfan treated groups was much lower than i.p. injection groups. Fertility was restored in mice treated with busulfan and donor-derived offspring were obtained after SSC transplantation. Our study indicated that intratesticular injection busulfan for the preparation of recipients in mice is safe and feasible.     

Astatine (211At) as a therapeutic radionuclide. The plasma: Blood cell distribution in vitro

Therapy of carcinoma of the thyroid may include the use of the radionuclide ¹³¹I, which localizes to thyroid tissue. In considering the use of another halogen, the α particle emitting radionuclide astatine, ²¹¹At, there is also the requirement that it too can be taken up by the thyroid. However, in view of its short half-life (7.2 h) it is important that its transport in the blood is not a factor likely to render it less available. For example, retention of ²¹¹At by red cells may retard its uptake by the thyroid. This in vitro in-vestigation of the partitioning of the ²¹¹At between erythrocytes and plasma indicates that it is not strongly bound by the red cells in blood.     

Histo-morphology of the thyroid gland during the larval development of Pleurodema borellii (Anura,Leptodactylidae)

The thyroid gland is essential in anurans, since thyroid hormones (TH) are the main regulators of larval development. Its absence or inactivity interrupts development and precludes metamorphosis. Histological changes are important diagnostic criteria for evaluating thyroid gland activity. However, there is a large larval diversity where the development of the thyroid gland development has not been studied. Pleurodema borellii is an anuran from northwest of Argentina with typical omnivorous pond tadpoles that can be easily raised in captivity. This study explores the histo-morphological changes of the thyroid gland architecture during larval development. Histological parameters indicate peak glandular activity in parallel with the intensity of the metamorphic transformations. These parameters regress towards the end of metamorphosis, indicating low TH release. P. borellii's thyroid gland does not appear to have relevant activity in post-metamorphic juvenile stages. This study is a first step towards understanding endocrine regulation during the development of Pleurodema borellii, and a reference to future studies in this species involving thyroid-dependent processes.     

Low vs. high radioiodine activity to ablate the thyroid after thyroidectomy for cancer: a randomized study

Background

Radioactive iodine is commonly administered following thyroidectomy for differentiated thyroid carcinoma to ablate the thyroid remnant. The optimal administered activity of radioiodine is unknown.

Methodology/Principal Findings

Adult subjects (n = 160) diagnosed with papillary or follicular thyroid carcinoma were randomly allocated to receive either 1100 MBq (30 mCi) or 3700 MBq (100 mCi) activity of radioiodine (¹³¹I) following thyroidectomy. The study participants were prepared for ablation using thyroid hormone withdrawal. Ablation was considered successful when serum thyroglobulin concentration was less than 1 ng/mL and no uptake was present in ¹³¹I scan. Ablation was successful following one administration of radioiodine in 42 (52%; 95% CI, 41% to 63%) of the 81 evaluable study participants who received 1100 MBq, and in 43 (56%, 45% to 67%) of the 77 subjects who received 3700 MBq activity (P = .61). There was no difference between the groups in the numbers of repeat radioiodine treatments needed to complete ablation (P = .27). The higher activity was associated with more nausea and taste disturbances, and a longer stay in a radioprotected isolation unit. None of the participants died from thyroid cancer during a median follow up of 51 months; three subjects in the 3700 MBq group and none in the 1100 MBq group were diagnosed with distant metastases during follow-up. In a meta-analysis of four randomized studies that compared the 1100 and 3700 MBq activities, the 1100 MBq activity tended to be associated with a higher risk of unsuccessful ablation (relative risk 1.148, 95% CI 0.974 to 1.353, P =  .10).

Conclusions/Significance

The results provide no conclusive evidence that 3700 MBq activity is more effective for ablation of the thyroid remnant than 1100 MBq activity. The 3700 MBq activity is associated with more adverse effects.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00115895","term_id":"NCT00115895"}}NCT00115895     

Changes in whole body concentrations of thyroid hormones and cortisol in metamorphosing conger eel

Summary To clarify the hormonal regulation of metamorphosis of the conger eel (Conger myriaster), changes in whole body concentrations of thyroid hormones, thyroxine (T₄) and triiodothyronine (T₃), and cortisol during metamorphosis were examined, as well as the changes in the histological activity of the thyroid gland. In larvae before metamorphosis, T₄ and T₃ levels were less than 5 and 0.15 ng·g^-1 respectively. Levels of T₄ increased to about 30 ng·g^-1 during early metamorphosis, and decreased subsequently. Levels of T₃ increased gradually in early metamorphosis, and then increased abruptly to about 2.0 ng·g^-1 in late metamorphosis. Before metamorphosis, cortisol levels of the leptocephali less than 11 cm in total length were greater than 200 ng·g^-1. Cortisol levels decreased rapidly in larger premetamorphic leptocephali, and low levels were maintained throughout the metamorphic period. Histological observation revealed an activation of the thyroid gland in early metamorphosis; thyroid follicle epithelial cells became columnar and their nuclei larger. Active uptake of colloid by these cells and intensive vascularization of the gland were also observed. By the end of metamorphosis, follicle epithelial cells became squamous, indicating a low level of glandular activity. These results suggest that thyroid hormone plays an important role in regulation of conger eel metamorphosis.Abbreviations AL anal length - TL total length - T ₃ triiodothyronine - T ₄ thyroxine     

Distribution of the lithium ion in endocrine organs of the rat

Lithium ions accumulated consistently in the pituitary and thyroid of rats at concentrations significantly greater than in plasma. There was also a significant, although lower, accumulation of Li⁺ in the adrenal gland. No accumulation of lithium ion was noted in the testis or in the ovary. The possible significance of these findings with regard to some of the side effects of lithium carbonate treatment is discussed.     

Investigation on Toxicity and Teratogenicity in Rats of a Retinoid‐Polyamine Conjugate with Potent Anti‐Inflammatory Properties

Previous studies have shown that N¹,N¹²‐bis(all‐trans‐retinoyl)spermine (RASP), a retinoid analog, inhibits RNase P activity and angiogenesis in the chicken embryo chorioallantoic membrane, demonstrates anti‐tumor activity on prostate cancer cells, and acts as anti‐inflammatory agent, being more effective and less toxic than all‐trans retinoic acid. In an attempt to further characterize the biological profile of RASP, we tested its effects on organ toxicity and teratogenicity by daily oral gavage of RASP at a level of 50 mg/Kg of body weight in two generations of rats. We found that this compound does not induce changes to the body growth, the appearance of physical features, and the animal's reflexes. Additionally, no substantial histopathological lesions were found in brain, heart, lung, thymus, liver, thyroid gland, adrenal gland, pituitary gland, kidneys, spleen, skin, femora, prostate, testis, epididymis, vagina, uterus, and ovaries of RASP‐treated animals. These results suggest RASP, as a promising lead compound for the treatment of several dermatological disorders and certain cancer types, has apparently minimal toxic side‐effects as revealed in this two‐generation reproduction study in rats.     

177Lu-DOTA-HH1, a Novel Anti-CD37 Radio-Immunoconjugate: A Study of Toxicity in Nude Mice

Background

CD37 is an internalizing B-cell antigen expressed on Non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia cells (CLL). The anti-CD37 monoclonal antibody HH1 was conjugated to the bifunctional chelator p-SCN-Bn-DOTA and labelled with the beta-particle emitting radionuclide ¹⁷⁷Lu creating the radio-immunoconjugate (RIC) ¹⁷⁷Lu-DOTA-HH1 (¹⁷⁷Lu-HH1, trade name Betalutin). The present toxicity study was performed prior to initiation of clinical studieswith ¹⁷⁷Lu-HH1.

Methodology/Principal Findings

Nude mice with or without tumor xenografts were treated with 50 to 1000 MBq/kg ¹⁷⁷Lu- HH1 and followed for clinical signs of toxicity up to ten months. Acute, life threatening bone marrow toxicity was observed in animals receiving 800 and 1000 MBq/kg ¹⁷⁷Lu-HH1. Significant changes in serum concentrations of liver enzymes were evident for treatment with 1000 MBq/kg ¹⁷⁷Lu-HH1. Lymphoid depletion, liver necrosis and atrophy, and interstitial cell hyperplasia of the ovaries were also observed for mice in this dose group.

Conclusions/Significance

¹⁷⁷Lu-DOTA-HH1 was well tolerated at dosages about 10 times above those considered relevant for radioimmunotherapy in patients with B-cell derived malignancies.The toxicity profile was as expected for RICs. Our experimental results have paved the way for clinical evaluation of ¹⁷⁷Lu-HH1 in NHL patients.     

Selenium in the anterior pituitary of the rat after a single injection of75Se sodium selenite

In order to investigate the selenite metabolism in the anterior pituitary and compare it with other endocrine organs, rats were injected intraperitoneally with⁷⁵Se sodium selenite (5 mg/kg). The rats were whole body counted shortly after injection and recounted just before sacrifice, which was performed 2, 24, 48 h, and 4, 10, 20, 30, 40, 60, and 80 d after injection. Besides the anterior pituitary, the selenium content was also estimated in the thyroid gland, testis, adrenals, liver, kidney, and blood. The maximum selenium content was observed in all organs 2 h after injection, at which time the anterior pituitary contained 2.9 μg/g wet wt, compared to 13.5 μ/g wet wt in liver and .6 μg/mg wet wt in testis. The excretion of selenite from the anterior pituitary resembled that seen in most other organs investigated, i.e., an initial rapid excretion and a slower secondary phase resembling a first order reaction. Practically all selenium was excreted by 60 d after injection.     

Evaluation of rat thyroid gland morphophysiological status after three months exposure to 50 Hz electromagnetic field

Objective of our study was to use morphophysiological criteria in order to determine the sensitivity of male rat thyroid gland to an extremely low frequency electromagnetic field (ELF-EMF) influence and the ability of the gland to repair after period of exposure. Animals were exposed to 50Hz, 50-500 microT ELF-EMF for 3 months when a part of them (group I) were sacrificed, while the rest of animals were subjected to recovery evaluation of the gland and sacrificed after 1 (group II), 2 (group III) and 3 (group IV) weeks. Histological and stereological analyses were performed on paraffin and semifine thyroid gland sections. Serum T3 and T4 were also determined. Histological and stereological analyses showed that the volume density of follicular epithelium and thyroid activation index decreased, while the volume density of colloid and capillary network increased in group I, II and III. The values of all these parameters in group IV were similar to corresponding controls. Serum T3 and T4 concentrations were significantly lower in all exposed animals, except in group I. Results of this study demonstrate that after significant morphophysiological changes caused by ELF-EMF exposure thyroid gland recovered morphologically, but not physiologically, during the investigated repair period.     

Synergic radiosensitization of sinomenine hydrochloride and radioiodine on human papillary thyroid carcinoma cells

Radioiodine (¹³¹I) therapy is an important treatment for thyroid carcinoma. The response to radiotherapy sometimes limited by the development of radioresistance. Sinomenine hydrochloride(SH), was reported as a prospective radiosensitizer. This study was aim to evaluate synergic radiosensitization of SH and ¹³¹I on papillary thyroid carcinoma (PTC). We evaluated HTori-3, BCPAP and TPC-1 cells, the cell viability was evaluated by MTT. The experiment was divided into 4 groups: control group, SH (0.8 mM) group, I (¹³¹I 14.8 MBq/ml) group and ISH (SH 0.8 mM plus ¹³¹I 14.8 MBq/ml) group. Flow cytometry was used to investigate cell cycle phases and cell apoptosis. RT-PCR and western blotting were performed to determine the molecular changes. Compared to control group, SH significantly increased apoptosis and enhanced radiosensitivity of HTori-3 and PTC cells were related to the ratio of Bcl-2 to Bax protein downregulation and Fas, p21, p-ATM, p-Chk1, p-Chk2 and p53 protein expression upregulation in the ISH group (P < 0.05). Our results indicate that synergic radiosensitization of SH and iodine-131 on PTC cells and SH could be a potential therapeutic radiosensitizer in PTC radio therapy after total thyroidectomy.     

粘细菌Corallococcus sp. strain EGB及其培养发酵液的安全性评估

【目的】研究粘细菌Corallococcus sp. strain EGB及其细胞培养发酵液的毒理安全性,为菌株EGB作为新型生防微生物菌剂的开发和环境施用安全性提供一定的科学基础。【方法】通过Ames试验、小鼠骨髓嗜多染红细胞微核试验和小鼠睾丸染色体畸变试验测定粘细菌EGB菌体及其细胞培养发酵液的遗传毒性;通过经口灌胃的方式测定粘细菌EGB菌体及其细胞培养发酵液对ICR小鼠的急性毒性和28d亚急性毒性。【结果】Ames试验、微核试验和精母细胞染色体畸变试验结果表明,与对照组相比,EGB菌体及其细胞培养发酵液无基因突变能力,对ICR小鼠无明显的遗传毒性。EGB菌体及其细胞培养发酵液对ICR小鼠的急性经口半致死剂量(LD50)>10g/kg BW (body weight);连续灌胃28 d后,处理组ICR小鼠的体重变化、采食饮水、血液生化指标、血常规、主要脏器指数和主要器官病理切片与对照组相比无显著差异(P<0.05)。【结论】粘细菌EGB菌体及其细胞培养发酵液的毒理安全性属于无毒类别,粘细菌的生物安全性使其在工农业领域的植物病害控制和生物转化等方面具有潜在的应用价值。     

Anti-CD45 Radioimmunotherapy with 90Y but Not 177Lu Is Effective Treatment in a Syngeneic Murine Leukemia Model

Radioimmunotherapy (RIT) for treatment of hematologic malignancies has primarily employed monoclonal antibodies (Ab) labeled with ¹³¹I or ⁹⁰Y which have limitations, and alternative radionuclides are needed to facilitate wider adoption of RIT. We therefore compared the relative therapeutic efficacy and toxicity of anti-CD45 RIT employing ⁹⁰Y and ¹⁷⁷Lu in a syngeneic, disseminated murine myeloid leukemia (B6SJLF1/J) model. Biodistribution studies showed that both ⁹⁰Y- and ¹⁷⁷Lu-anti-murine CD45 Ab conjugates (DOTA-30F11) targeted hematologic tissues, as at 24 hours 48.8±21.2 and 156±14.6% injected dose per gram of tissue (% ID/g) of ⁹⁰Y-DOTA-30F11 and 54.2±9.5 and 199±11.7% ID/g of ¹⁷⁷Lu-DOTA-30F11 accumulated in bone marrow (BM) and spleen, respectively. However, ⁹⁰Y-DOTA-30F11 RIT demonstrated a dose-dependent survival benefit: 60% of mice treated with 300 µCi ⁹⁰Y-DOTA-30F11 lived over 180 days after therapy, and mice treated with 100 µCi ⁹⁰Y-DOTA-30F11 had a median survival 66 days. ⁹⁰Y-anti-CD45 RIT was associated with transient, mild myelotoxicity without hepatic or renal toxicity. Conversely, ¹⁷⁷Lu- anti-CD45 RIT yielded no long-term survivors. Thus, ⁹⁰Y was more effective than ¹⁷⁷Lu for anti-CD45 RIT of AML in this murine leukemia model.     

Influence of dietary selenium on metabolism of cadmium and mercury in reproductive tissues of rats

Dietary selenium supplementation for rats resulted in a greater deposition of ¹⁰⁹Cd in testis, but caused decreased deposition of the isotope in seminal vesicles, epididymis and prostate gland. In contrast, dietary selenium caused increased deposition of ²⁰³Hg in seminal vesicles and prostate gland but drastically reduced the levels of this radioisotope in testis and epididymis. Selenium diverted the binding of ¹⁰⁹Cd in cytosols in testis, seminal vesicles, epididymis and prostate gland, but had minimal effects on the binding of ²⁰³Hg in these reproductive organs. Selenium deficiency caused increased excretion of ¹⁰⁹Cd in feces and urine, and increased excretion of ²⁰³Hg in urine of rats. The biological half-lives of the two radioisotopes in the −Se and +Se rats were calculated to be, respectively, 202 and 219 days for ¹⁰⁹Cd, and 2 and 6 days for ²⁰³Hg.     

Catechin induced modulation in the activities of thyroid hormone synthesizing enzymes leading to hypothyroidism

Catechins, the flavonoids found in abundance in green tea, have many beneficial health effects such as antioxidative, anticarcinogenic, anti-inflammatory, antiallergic, and hypotensive properties. However, flavonoids have antithyroid/goitrogenic effect, although less information is available about the effect of pure catechin on thyroid physiology. The present investigation has been undertaken to explore the effect of catechin administration on thyroid physiology in rat model. For the in vivo experiment catechin was injected intraperitoneally (i.p.) at doses of 10, 20 and 30 mg/kg body to male albino rats for 15 and 30 days, respectively, and thyroid activities were evaluated with respect to determination of serum levels of thyroid hormones, thyroid peroxidase, 5′-deiodinase I (5′-DI), and Na⁺, K⁺-ATPase activities that are involved in the synthesis of thyroid hormone. Catechin decreased the activities of thyroid peroxidase and thyroidal 5′-deiodinase I, while Na⁺, K⁺-ATPase activity significantly increased in dose-dependent manner; substantial decrease in serum T3 and T4 levels coupled with significant elevation of serum TSH were also noted. Histological examinations of the thyroid gland revealed marked hypertrophy and/or hyperplasia of the thyroid follicles with depleted colloid content. In in vitro study, short-term exposure of rat thyroid tissue to catechin at the concentrations of 0.10, 0.20, and 0.30 mg/ml leads to decrease in the activities of thyroid peroxidase and 5′-deiodinase I, while the activity of thyroidal Na⁺, K⁺-ATPase remains unaltered even at high concentration of catechin treatment. The present study reinforces the concept that catechin, tea flavonoids possess potent antithyroid activity as evidenced from in vivo and in vitro studies.     

Targeted Cancer Therapy with a Novel Anti-CD37 Beta-Particle Emitting Radioimmunoconjugate for Treatment of Non-Hodgkin Lymphoma

¹⁷⁷Lu-DOTA-HH1 (¹⁷⁷Lu-HH1) is a novel anti-CD37 radioimmunoconjugate developed to treat non-Hodgkin lymphoma. Mice with subcutaneous Ramos xenografts were treated with different activities of ¹⁷⁷Lu-HH1, ¹⁷⁷Lu-DOTA-rituximab (¹⁷⁷Lu-rituximab) and non-specific ¹⁷⁷Lu-DOTA-IgG₁ (¹⁷⁷Lu-IgG₁) and therapeutic effect and toxicity of the treatment were monitored. Significant tumor growth delay and increased survival of mice were observed in mice treated with 530 MBq/kg ¹⁷⁷Lu-HH1 as compared with mice treated with similar activities of ¹⁷⁷Lu-rituximab or non-specific ¹⁷⁷Lu-IgG1, 0.9% NaCl or unlabeled HH1. All mice injected with 530 MBq/kg of ¹⁷⁷Lu-HH1 tolerated the treatment well. In contrast, 6 out of 10 mice treated with 530 MBq/kg ¹⁷⁷Lu-rituximab experienced severe radiation toxicity. The retention of ¹⁷⁷Lu-rituximab in organs of the mononuclear phagocyte system was longer than for ¹⁷⁷Lu-HH1, which explains the higher toxicity observed in mice treated with ¹⁷⁷Lu-rituximab. In vitro internalization studies showed that ¹⁷⁷Lu-HH1 internalizes faster and to a higher extent than ¹⁷⁷Lu-rituximab which might be the reason for the better therapeutic effect of ¹⁷⁷Lu-HH1.