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Systemic radioimmunotherapy (RIT) is arguably the most effective and least toxic anticancer treatment for non-Hodgkin lymphoma (NHL). In treatment-naïve patients with indolent NHL, the efficacy of a single injection of RIT compares with that of multiple cycles of combination chemotherapy. However, 20 years following the approval of the first CD20-targeting radioimmunoconjugates 90 Y-Ibritumomab-tiuxetan (Zevalin) and 131 I-tositumomab (Bexxar), the number of patients referred for RIT in western countries has dramatically decreased. Notwithstanding this, the development of RIT has continued. Therapeutic targets other than CD20 have been identified, new vector molecules have been produced allowing for faster delivery of RIT to the target, and innovative radionuclides with favorable physical characteristics such as alpha emitters have been more widely available. In this article, we reviewed the current status of RIT in NHL, with particular focus on recent clinical and preclinical developments., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: [ 177 Lu]Lu-lilotomab satetraxetan, a novel CD37 directed radioimmunotherapy (RIT), has been investigated in a first-in-human phase 1/2a study for relapsed indolent non-Hodgkin lymphoma. In this study, new methods were assessed to calculate the mean absorbed dose to the total tumor volume, with the aim of establishing potential dose-response relationships based on 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET) parameters and clinical response. Our second aim was to study if higher total tumor burden induces reduction in the 177 Lu-lilotomab satetraxetan accumulation in tumor., Procedures: Fifteen patients with different pre-dosing (non-radioactive lilotomab) regimens were included and the cohort was divided into low and high non-radioactive lilotomab pre-dosing groups for some of the analyses. 177 Lu-lilotomab satetraxetan was administered at dosage levels of 10, 15, or 20 MBq/kg. Mean absorbed doses to the total tumor volume (tTAD) were calculated from posttreatment single-photon emission tomography (SPECT)/computed tomography (CT) acquisitions. Total values of metabolic tumor volume (tMTV), total lesion glycolysis (tTLG) and the percent change in these parameters were calculated from FDG PET/CT performed at baseline, and at 3 and 6 months after RIT. Clinical responses were evaluated at 6 months as complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease (PD)., Results: Significant decreases in tMTV and tTLG were observed at 3 months for patients receiving tTAD ≥ 200 cGy compared to patients receiving tTAD < 200 cGy (p = .03 for both). All non-responders had tTAD < 200 cGy. Large variations in tTAD were observed in responders. Reduction in 177 Lu-lilotomab satetraxetan uptake in tumor volume was not observed in patients with higher baseline tumor burden (tTMV)., Conclusion: tTAD of ≥ 200 cGy may prove valuable to ensure clinical response, but further studies are needed to confirm this in a larger patient population. Furthermore, this work indicates that higher baseline tumor burden (up to 585 cm 3 ) did not induce reduction in radioimmunoconjugate accumulation in tumor., (© 2022. The Author(s).)

Background and Purpose: PARP inhibitors have been shown to increase the efficacy of radiotherapy in preclinical models. Radioimmunotherapy results in selective radiation cytotoxicity of targeted tumour cells. Here we investigate the combined effect of anti-CD37 β-emitting 177Lu-NNV003 radioimmunotherapy and the PARP inhibitor olaparib, and gene expression profiles in CD37 positive non-Hodgkin's lymphoma cell lines., Materials and Methods: The combined effect of 177Lu-NNV003 and olaparib was studied in seven cell lines using a fixed-ratio ray design, and combination index was calculated for each combination concentration. mRNA was extracted before and after treatment with the drug combination. After RNA-sequencing, hierarchical clustering was performed on basal gene expression profiles and on differentially expressed genes after combination treatment from baseline. Functional gene annotation analysis of significant differentially expressed genes after combination treatment was performed to identify enriched biological processes., Results: The combination of olaparib and 177Lu-NNV003 was synergistic in four of seven cell lines, antagonistic in one and both synergistic and antagonistic (conditionally synergistic) in two, depending on the concentration ratio between olaparib and 177Lu-NNV003. Cells treated with the combination significantly overexpressed genes in the TP53 signalling pathway. However, cluster analysis did not identify gene clusters that correlate with the sensitivity of cells to single agent or combination treatment., Conclusion: The cytotoxic effect of the combination of the PARP inhibitor olaparib and the β-emitting radioimmunoconjugate 177Lu-NNV003 was synergistic in the majority of tested lymphoma cell lines., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: MMM, AFM, SP, HH, JD and ARL are or where employed by Nordic Nanovector at the time the studies took place. ARL, TS, HH and JD own shares in Nordic Nanovector. AK is a member of the Scientific Advisory Board of Nordic Nanovector ASA. BM received an hourly-based salary payment from Nordic Nanovector ASA for his work on this article. This does not alter our adherence to PLOS ONE policies on sharing data and materials. No other potential conflicts of interest relevant to this article exist.

Background: The aim of this study was to investigate dosimetry data and clinical variables to predict hematological toxicity in non-Hodgkin lymphoma (NHL) patients treated with [ 177 Lutetium]Lu-lilotomab satetraxetan., Material and Methods: A total of 17 patients treated with [ 177 Lu]Lu-lilotomab satetraxetan in a first-in-human phase 1/2a study were included. Absorbed dose to the red marrow was explored using SPECT/CT-imaging of the lumbar vertebrae L2-L4 over multiple time points. Percentage reduction of thrombocytes and neutrophils at nadir compared to baseline (PBN) and time to nadir (TTN) were chosen as indicators of myelosuppression and included as dependent variables. Two models were applied in the analysis, a multivariate linear model and a sigmoidal description of toxicity as a function of absorbed dose. A total of 10 independent patient variables were investigated in the multivariate analysis., Results: Absorbed dose to the red marrow ranged from 1 to 4 Gy. Absorbed dose to the red marrow was found to be the only significant variable for PBN for both thrombocytes and neutrophils. The sigmoid function gave similar results in terms of accuracy when compared to the linear model., Conclusion: Myelosuppression in the form of thrombocytopenia and neutropenia in patients treated with [ 177 Lu]Lu-lilotomab satetraxetan can be predicted from the SPECT/CT-derived absorbed dose estimate to the red marrow.

Purpose: 177 Lu-lilotomab satetraxetan targets the CD37 antigen and has been investigated in a first-in-human phase 1/2a study for relapsed non-Hodgkin lymphoma (NHL). Tumor dosimetry and response evaluation can be challenging after radioimmunotherapy (RIT). Changes in FDG PET/CT parameters after RIT and correlations with tumor-absorbed doses has not been examined previously in patients with lymphoma. Treatment-induced changes were measured at FDG PET/CT and ceCT to evaluate response at the lesion level after treatment, and correlations with tumor-absorbed doses were investigated., Methods: Forty-five tumors in 16 patients, with different pre-treatment and pre-dosing regimens, were included. Dosimetry was performed based on multiple SPECT/CT images. FDG PET/CT was performed at baseline and at 3 and 6 months. SUV max , MTV, TLG, and changes in these parameters were calculated for each tumor. Lesion response was evaluated at 3 and 6 months (PET 3months and PET 6months ) based on Deauville criteria. Anatomical changes based on ceCT at baseline and at 6 and 12 months were investigated by the sum of perpendiculars (SPD)., Results: Tumor-absorbed doses ranged from 35 to 859 cGy. Intra- and interpatient variations were observed. Mean decreases in PET parameters from baseline to 3 months were ΔSUV max-3months 61%, ΔMTV 3months 80%, and ΔTLG 3months 77%. There was no overall correlation between tumor-absorbed dose and change in FDG PET or ceCT parameters at the lesion level or significant difference in tumor-absorbed doses between metabolic responders and non-responders after treatment., Conclusion: Our analysis does not show any correlation between tumor-absorbed doses and changes in FDG PET or ceCT parameters for the included lesions. The combination regimen, including cold antibodies, may be one of the factors precluding such a correlation. Increased intra-patient response with increased tumor-absorbed doses was observed for most patients, implying individual variations in radiation sensitivity or biology., Trial Registration: ClinicalTrials.gov Identifier (NCT01796171). Registered December 2012.

For patients with indolent non-Hodgkin lymphoma who fail initial anti-CD20-based immunochemotherapy or develop relapsed or refractory disease, there remains a significant unmet clinical need for new therapeutic approaches to improve outcomes and quality of life. 177Lu-lilotomab satetraxetan is a next-generation single-dose CD37-directed radioimmunotherapy (RIT) which was investigated in a phase 1/2a study in 74 patients with relapsed/refractory indolent non-Hodgkin B-cell lymphoma, including 57 patients with follicular lymphoma (FL). To improve targeting of 177Lu-lilotomab satetraxetan to tumor tissue and decrease hematologic toxicity, its administration was preceded by the anti-CD20 monoclonal antibody rituximab and the "cold" anti-CD37 antibody lilotomab. The most common adverse events (AEs) were reversible grade 3/4 neutropenia (31.6%) and thrombocytopenia (26.3%) with neutrophil and platelet count nadirs 5 to 7 weeks after RIT. The most frequent nonhematologic AE was grade 1/2 nausea (15.8%). With a single administration, the overall response rate was 61% (65% in patients with FL), including 30% complete responses. For FL with ≥2 prior therapies (n = 37), the overall response rate was 70%, including 32% complete responses. For patients with rituximab-refractory FL ≥2 prior therapies (n = 21), the overall response rate was 67%, and the complete response rate was 24%. The overall median duration of response was 13.6 months (32.0 months for patients with a complete response). 177Lu-lilotomab satetraxetan may provide a valuable alternative treatment approach in relapsed/refractory non-Hodgkin lymphoma, particularly in patients with comorbidities unsuitable for more intensive approaches. This trial was registered at www.clinicaltrials.gov as #NCT01796171., (© 2020 by The American Society of Hematology.)

Relapse of chronic lymphocytic leukaemia and non-Hodgkin's lymphoma after standard of care treatment is common and new therapies are needed. The targeted alpha therapy with 212Pb-NNV003 presented in this study combines cytotoxic α-particles from 212Pb, with the anti-CD37 antibody NNV003, targeting B-cell malignancies. The goal of this study was to explore 212Pb-NNV003 for treatment of CD37 positive chronic lymphocytic leukaemia and non-Hodgkin's lymphoma in preclinical mouse models.An anti-proliferative effect of 212Pb-NNV003 was observed in both chronic lymphocytic leukaemia (MEC-2) and Burkitt's lymphoma (Daudi) cells in vitro. In biodistribution experiments, accumulation of 212Pb-NNV003 was 23%ID/g and 16%ID/g in Daudi and MEC-2 tumours 24 h post injection. In two intravenous animal models 90% of the mice treated with a single injection of 212Pb-NNV003 were alive 28 weeks post cell injection. Median survival times of control groups were 5-9 weeks. There was no significant difference between different specific activities of 212Pb-NNV003 with regards to therapeutic effect or toxicity. For therapeutically effective activities, a transient haematological toxicity was observed. This study shows that 212Pb-NNV003 is effective and safe in preclinical models of CD37 positive chronic lymphocytic leukaemia and non-Hodgkin's lymphoma, warranting future clinical testing., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: JD and HH are employees and shareholders of Nordic Nanovector ASA. AFM is a PhD student employed by Nordic Nanovector ASA, funded by the Norwegian Research Council. AK is a member of the Scientific Advisory Board of Nordic Nanovector ASA. AS is employed by Orano Med SAS, TARS and JT are employed by Orano Med LLC. Patents: PCT/EP2011/051231 (Radioimmunoconjugates and uses thereof), PCT/EP2014/061824 (Method for upregulating antigen expression), PCT/EP2017/073336 (Treatment of non-Hodgkin lymphoma using lilotomab and 177Lu-lilotomab satetraxetan), PCT/EP2018/082065 (Radioimmunoconjugates in combination with other drugs as treatment against NHL), EP2854870B1 (Method and apparatus for the production of lead 212 for medical use), EP3174068B1 (New method and apparatus for the production of high purity radionuclides). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose: The aim of this study was to explore the β-emitting lutetium-177 labelled anti-CD37 antibody NNV003 ( 177 Lu-NNV003, Humalutin®) for the treatment of non-Hodgkin's lymphoma in in vitro studies and in animal models., Methods: Cytotoxicity of 177 Lu-NNV003 was measured in REC-1 (mantle cell lymphoma) and DOHH-2 (diffuse large B cell lymphoma) cell lines. Biodistribution was studied in mice bearing subcutaneous DOHH-2 or MEC-2 (chronic lymphocytic leukaemia) xenografts. The therapeutic effect of a single injection of 177 Lu-NNV003 was measured in mice intravenously or subcutaneously injected with REC-1 cells. Haematological and histopathological assessments were used to evaluate the toxic effect of 177 Lu-NNV003. The immunotherapeutic effect of NNV003 was assessed by measuring binding to Fcγ receptors, activation of ADCC and ADCP. NNV003's immunogenicity potential was assessed using in silico immunogenicity prediction tools., Results: 177 Lu-NNV003 showed an activity dependent antiproliferative effect in all cell lines. Maximum tumour uptake in vivo was 45% of injected activity/g in MEC-2 tumours and 15% injected activity/g in DOHH-2 tumours. In mice injected intravenously with REC-1 cells, 177 Lu-NNV003 (50-100 MBq/kg) improved survival compared to control groups (p < 0.02). In mice with subcutaneous REC-1 xenografts, 500 MBq/kg 177 Lu-NNV003 extended survival compared to the control treatments (p < 0.005). Transient haematological toxicity was observed in all mice treated with radioactivity. NNV003 induced ADCC and ADCP and was predicted to have a lower immunogenicity potential than its murine counterpart., Conclusion: 177 Lu-NNV003 had a significant anti-tumour effect and a favourable toxicity profile. These results warrant further clinical testing in patients with CD37-expressing B cell malignancies.

Checkpoint blockade can reverse T-cell exhaustion and promote antitumor responses. Although blocking the PD-1 pathway has been successful in Hodgkin lymphoma, response rates have been modest in B-cell non-Hodgkin lymphoma (NHL). Coblockade of checkpoint receptors may therefore be necessary to optimize antitumor T-cell responses. Here, characterization of coinhibitory receptor expression in intratumoral T cells from different NHL types identified TIGIT and PD-1 as frequently expressed coinhibitory receptors. Tumors from NHL patients were enriched in CD8 + and CD4 + T effector memory cells that displayed high coexpression of TIGIT and PD-1, and coexpression of these checkpoint receptors identified T cells with reduced production of IFNγ, TNFα, and IL2. The suppressed cytokine production could be improved upon in vitro culture in the absence of ligands. Whereas PD-L1 was expressed by macrophages, the TIGIT ligands CD155 and CD112 were expressed by lymphoma cells in 39% and 50% of DLBCL cases and in some mantle cell lymphoma cases, as well as by endothelium and follicular dendritic cells in all NHLs investigated. Collectively, our results show that TIGIT and PD-1 mark dysfunctional T cells and suggest that TIGIT and PD-1 coblockade should be further explored to elicit potent antitumor responses in patients with NHL., (©2019 American Association for Cancer Research.)

Purpose: 177 Lu-lilotomab satetraxetan is a novel anti-CD37 antibody radionuclide conjugate for the treatment of non-Hodgkin lymphoma (NHL). Four arms with different combinations of pre-dosing and pre-treatment have been investigated in a first-in-human phase 1/2a study for relapsed CD37+ indolent NHL. The aim of this work was to determine the tumor and normal tissue absorbed doses for all four arms, and investigate possible variations in the ratios of tumor to organs-at-risk absorbed doses., Methods: Two of the phase 1 arms included cold lilotomab pre-dosing (arm 1 and 4; 40 mg fixed and 100 mg/m 2 BSA dosage, respectively) and two did not (arms 2 and 3). All patients were pre-treated with different regimens of rituximab. The patients received either 10, 15, or 20 MBq 177 Lu-lilotomab satetraxetan per kg body weight. Nineteen patients were included for dosimetry, and a total of 47 lesions were included. The absorbed doses were calculated from multiple SPECT/CT-images and normalized by administered activity for each patient. Two-sided Student's t tests were used for all statistical analyses., Results: Organs with distinct uptake of 177 Lu-lilotomab satetraxetan, in addition to tumors, were red marrow (RM), liver, spleen, and kidneys. The mean RM absorbed doses were 0.94, 1.55, 1.44, and 0.89 mGy/MBq for arms 1-4, respectively. For the patients not pre-dosed with lilotomab (arms 2 and 3 combined) the mean RM absorbed dose was 1.48 mGy/MBq, which was significantly higher than for both arm 1 (p = 0.04) and arm 4 (p = 0.02). Of the other organs, the highest uptake was found in the spleen, and there was a significantly lower spleen absorbed dose for arm-4 patients than for the patient group without lilotomab pre-dosing (1.13 vs. 3.20 mGy/MBq; p < 0.01). Mean tumor absorbed doses were 2.15, 2.31, 1.33, and 2.67 mGy/MBq for arms 1-4, respectively. After averaging the tumor absorbed dose for each patient, the patient mean tumor absorbed dose to RM absorbed dose ratios were obtained, given mean values of 1.07 for the patient group not pre-dosed with lilotomab, of 2.16 for arm 1, and of 4.62 for arm 4. The ratios were significantly higher in both arms 1 and 4 compared to the group without pre-dosing (p = 0.05 and p = 0.02). No statistically significant difference between arms 1 and 4 was found., Conclusions: RM is the primary dose-limiting organ for 177 Lu-lilotomab satetraxetan treatment, and pre-dosing with lilotomab has a mitigating effect on RM absorbed dose. Increasing the amount of lilotomab from 40 mg to 100 mg/m 2 was found to slightly decrease the RM absorbed dose and increase the ratio of tumor to RM absorbed dose. Still, both pre-dosing amounts resulted in significantly higher tumor to RM absorbed dose ratios. The findings encourage continued use of pre-dosing with lilotomab.

Red marrow (RM) is often the primary organ at risk in radioimmunotherapy; irradiation of marrow may induce short- and long-term hematologic toxicity. 177 Lu-lilotomab satetraxetan is a novel anti-CD37 antibody-radionuclide conjugate currently in phase 1/2a. Two predosing regimens have been investigated, one with 40 mg of unlabeled lilotomab antibody (arm 1) and one without (arm 2). The aim of this work was to compare RM-absorbed doses for the two arms and to correlate absorbed doses with hematologic toxicity., Methods: Eight patients with relapsed CD37+ indolent B-cell non-Hodgkin lymphoma were included for RM dosimetry. Hybrid SPECT and CT images were used to estimate the activity concentration in the RM of L2-L4. Pharmacokinetic parameters were calculated after measurement of the 177 Lu-lilotomab satetraxetan concentration in blood samples. Adverse events were graded according to the Common Terminology Criteria for Adverse Events, version 4.0., Results: The mean absorbed doses to RM were 0.9 mGy/MBq for arm 1 (lilotomab+) and 1.5 mGy/MBq for arm 2 (lilotomab-). There was a statistically significant difference between arms 1 and 2 (Student t test, P = 0.02). Total RM-absorbed doses ranged from 67 to 127 cGy in arm 1 and from 158 to 207 cGy in arm 2. For blood, the area under the curve was higher with lilotomab predosing than without (P = 0.001), whereas the volume of distribution and the clearance of 177 Lu-lilotomab satetraxetan was significantly lower (P = 0.01 and P = 0.03, respectively). Patients with grade 3/4 thrombocytopenia had received significantly higher radiation doses to RM than patients with grade 1/2 thrombocytopenia (P = 0.02). A surrogate, non-imaging-based, method underestimated the RM dose and did not show any correlation with toxicity., Conclusion: Predosing with lilotomab reduces the RM-absorbed dose for 177 Lu-lilotomab satetraxetan patients. The decrease in RM dose could be explained by the lower volume of distribution. Hematologic toxicity was more severe for patients receiving higher absorbed radiation doses, indicating that adverse events possibly can be predicted by the calculation of absorbed dose to RM from SPECT/CT images., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

177 Lu-lilotomab satetraxetan is a novel antibody radionuclide conjugate currently tested in a phase 1/2a first-in-human dosage escalation trial for patients with relapsed CD37+ indolent non-Hodgkin lymphoma. The aim of this work was to develop dosimetric methods and calculate tumor-absorbed radiation doses for patients treated with 177 Lu-lilotomab satetraxetan., Methods: Patients were treated at escalating injected activities (10, 15 and 20 MBq/kg) of 177 Lu-lilotomab satetraxetan and with different predosing, with or without 40 mg of unlabeled lilotomab. Eight patients were included for the tumor dosimetry study. Tumor radioactivity concentrations were calculated from SPECT acquisitions at multiple time points, and tumor masses were delineated from corresponding CT scans. Tumor-absorbed doses were then calculated using the OLINDA sphere model. To perform voxel dosimetry, the SPECT/CT data and an in-house-developed MATLAB program were combined to investigate the dose rate homogeneity., Results: Twenty-six tumors in 8 patients were ascribed a mean tumor-absorbed dose. Absorbed doses ranged from 75 to 794 cGy, with a median of 264 cGy across different dosage levels and different predosing. A significant correlation between the dosage level and tumor-absorbed dose was found. Twenty-one tumors were included for voxel dosimetry and parameters describing dose-volume coverage calculated. The investigation of intratumor voxel doses indicates that mean tumor dose is correlated to these parameters., Conclusion: Tumor-absorbed doses for patients treated with 177 Lu-lilotomab satetraxetan are comparable to doses reported for other radioimmunotherapy compounds. Although the intertumor variability was considerable, a correlation between tumor dose and patient dosage level was found. Our results indicate that mean dose may be used as the sole dosimetric parameter on the lesion level., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

This national population-based study aimed to investigate conditional survival and standardized mortality ratios (SMR) after high-dose therapy with autologous stem-cell transplantation (HDT-ASCT) for non-Hodgkin lymphoma (NHL), and to analyse cause of death, relapses and second malignancies. All patients ≥18 years treated with HDT-ASCT for NHL in Norway between 1987 and 2008 were included (n = 578). Information from the Cause of Death Registry and Cancer Registry of Norway were linked with clinical data. The 5-, 10- and 20-year overall survival was 61% (95% confidence interval [CI] 56-64%), 52% (95%CI 48-56%) and 45% (95%CI 40-50%), respectively. The 5-year survival conditional on having survived 2, 5 and 10 years after HDT-ASCT was 81%, 86% and 93%. SMRs were 12·3 (95%CI 11·0-13·9), 4·9 (95%CI 4·1-5·9), 2·4 (95%CI 1·8-3·2) and 1·0 (95%CI 0·6-1·8) for the entire cohort and for patients having survived 2, 5 and 10 years after HDT-ASCT respectively. Of the 281 deaths observed, 77% were relapse-related. Treatment-related mortality was 3·6%. The 10-year cumulative incidence of second malignancies was 7·9% and standardized incidence ratio was 2·0 (95%CI 1·5-2·6). NHL patients treated with HDT-ASCT were at increased risk of second cancer and premature death. The mortality was still elevated at 5 years, but after 10 years mortality equalled that of the general population., (© 2016 John Wiley & Sons Ltd.)

High dose chemotherapy with autologous stem cell transplant (HD-ASCT) is a recommended procedure for patients with transformed indolent B-cell lymphoma from the pre-rituximab era. In this retrospective single-center study, we present our experience with HD-ASCT in patients with histologically verified transformed indolent B-cell lymphoma in the rituximab era. Forty-two patients were included, of whom 28 with chemosensitive disease proceeded to HD-ASCT. Twenty patients (71%) achieved a complete response (CR) and five (18%) a partial response (PR) after HD-ASCT. With a median observation time of 49 months for the survivors, the median progression-free survival (PFS) and overall survival (OS) for patients with HD-ASCT were 39 months and 57 months, respectively. Patients who were rituximab-naive at transformation had a significantly better OS compared to patients previously treated with rituximab, both in the whole patient cohort and among the HD-ASCT-treated patients (p = 0.036 and p = 0.039, respectively). Furthermore, male sex influenced survival negatively, whereas time from diagnosis to transformation was positively associated with survival, both with borderline significance, in HD-ASCT-treated patients. In conclusion, HD-ASCT remains an effective treatment for transformed indolent lymphomas in the rituximab era.

The monoclonal antibody against CD20, rituximab, alone, or as part of combination therapies, is standard therapy for non-Hodgkin's B-cell lymphoma. Despite significantly better clinical results obtained for beta-emitting radioimmunoconjugates (RICs), RICs targeting CD20 are not commonly used in medical practice, partly because of competition for the CD20 target. Therefore, novel therapeutic approaches against other antigens are intriguing. Here, the binding properties of a novel antibody against CD37 (tetulomab) were compared with those of rituximab. The therapeutic effect of (177)Lu-tetulomab was compared with (177)Lu-rituximab on Daudi cells in vitro. The biodistribution, therapeutic and toxic effects of (177)Lu-tetulomab and unlabeled tetulomab were determined in SCID mice injected with Daudi cells. The affinity of tetulomab to CD37 was similar to the affinity of rituximab to CD20, but the CD37-tetulomab complex was internalized 10-times faster than the CD20-rituximab complex. At the same concentration of antibody, (177)Lu-tetulomab was significantly more efficient in inhibiting cell growth than was (177)Lu-rituximab, even though the cell-bound activity of (177)Lu-rituximab was higher. Treatment with 50 and 100 MBq/kg (177)Lu-tetulomab resulted in significantly increased survival of mice, compared with control groups treated with tetulomab or saline. The CD37 epitope recognized by tetulomab was highly expressed in 216 out of 217 tumor biopsies from patients with B-cell lymphoma. This work warrants further pre-clinical and clinical studies of (177)Lu-tetulomab.