Crosses represent censored animals that were euthanized before reaching 4 times the initial tumor volume

Crosses represent censored animals that were euthanized before reaching 4 times the initial tumor volume. 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. 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. Introduction Despite the promise of therapy using the naked monoclonal antibody (mAb) rituximab, a substantial number Sodium phenylbutyrate of the patients treated with conventional doses of rituximab alone or in combination with chemotherapy do not obtain complete response and may eventually relapse [1]. Alternative treatments have been anti-CD20 mAbs conjugated to 131I (tositumomab) or 90Y (ibritumomab-tiuxetan). Treatment with conventional activities of the radiolabeled mAbs has produced higher overall response and complete remission rates compared with naked mAbs [2C5]. Mouse monoclonal to CD41.TBP8 reacts with a calcium-dependent complex of CD41/CD61 ( GPIIb/IIIa), 135/120 kDa, expressed on normal platelets and megakaryocytes. CD41 antigen acts as a receptor for fibrinogen, von Willebrand factor (vWf), fibrinectin and vitronectin and mediates platelet adhesion and aggregation. GM1CD41 completely inhibits ADP, epinephrine and collagen-induced platelet activation and partially inhibits restocetin and thrombin-induced platelet activation. It is useful in the morphological and physiological studies of platelets and megakaryocytes.
Considering that radioimmunotherapy (RIT) is mostly used after patients have been treated with several rounds of rituximab and that the two approved radioimmunoconjugates (RICs) for clinical use, 90Y-ibritumomab-tiuxetan (Zevalin) and 131I-tositumomab (Bexxar), target the Sodium phenylbutyrate same CD20 antigen as rituximab, it is desirable to design a new RIC that will target a different antigen than CD20. The CD37 antigen is abundantly expressed in B-cells, but is absent on plasma cells and normal stem cells [6C8]. Therefore, CD37 seems to be an appropriate therapeutic target in patients with relapsed B-cell derived malignancies, such as B-cell CLL, hairy-cell leukemia (HCL) and B-cell NHL. RIT with CD37 as target has previously been explored using a 131I-labeled murine monoclonal antibody (MB-1) both in a mouse model and in patients [9C14]. A higher degree of internalization and degradation of 131I-labeled RIC was found for CD37 than for CD20 [14]. Despite promising clinical responses observed in these clinical studies for the anti-CD37 antibody, further development of RIT focused on CD20 as the target antigen and no subsequent efforts have been made to develop RIT with anti-CD37-based RICs. A limited number of other CD37-directed antibody based immunotherapies have, however, been evaluated in patients. The small modular immunopharmaceutical protein Otlertuzumab has advanced into clinical testing [15] and recently reported on phase II data in combination with bendamustine [16]. In addition, the Fc-engineered antibody CD37.1 (BI836826) [17] has recently entered phase I [18]. Furthermore, two antibody-drug conjugates (ADCs) have been developed that covalently link cytotoxic agents to CD37-targeting antibodies to enhance their antitumor potency: IMGN529 [19] and AGS-67E [20]. ADCs are designed to give specific delivery of cytotoxic compounds to cells expressing the target antigen, through ADC binding, internalization, and intracellular payload release. Clinical data have demonstrated the potential of ADCs for cancer therapy of CD30 and HER2 positive tumors [21,22]. All these CD37 targeting drugs had shown promising results, which further validates CD37 as a target for treatment of NHL and CLL. An advantage with RIT Sodium phenylbutyrate compared with naked mAbs and ADCs is the range of the emitted radiation, which gives a cross-fire effect so that tumor cells with less antigens or non-accessible tumor cells also get hit by the cytotoxic radiation. It remains to be seen if the mechanism of action of RIT is better than that of ADCs. The potency of RIT against the internalizing antigen CD37 might have been underestimated by the use of the radionuclide 131I, which tends to be cleaved off from the antibody and Sodium phenylbutyrate excreted from the cells upon internalization and catabolism when used as non-residualizing tyrosine-incorporated radiolabel, as was done in the early studies with 131I-MB-1 [23]. Residualizing radiolabels, on the other hand, are trapped in the cells after metabolism of the RIC. In an effort to re-evaluate and improve RIT against CD37 we have developed a new RIC (Betalutin) based on the residualizing radiolabel 177Lu linked to the anti-CD37 antibody HH1 [24]. Treatment with 100 MBq/kg 177Lu-HH1 resulted in a threefold increase in the survival of SCID mice that were intravenously injected with Daudi lymphoma cells compared to untreated control mice [7]. SCID mice are not able to repair DNA double strand breaks [25], limiting the amount of radioactivity that can be administered, while nude mice can tolerate higher doses of radiation. A subcutaneous tumor xenograft Sodium phenylbutyrate in nude mice is a more relevant model for the bulky type of disease that is often found in NHL patients than the intravenous model in SCID mice. Therefore, the therapeutic and toxicity effect of 177Lu-HH1 was evaluated in nude mice with subcutaneous Ramos xenografts in the present paper. Materials and Methods Tumor cells Ramos lymphoma cells (LGC Standards,.